USOO698.6901B2 (12) United States Patent (10) Patent No.: US 6,986,901 B2 Meisel et al. (45) Date of Patent: Jan. 17, 2006 (54) GASTROINTESTINAL COMPOSITIONS 6,121,301 A 9/2000 Nagasawa et al. 6,127,418 A 10/2000 Bueno et al. (75) Inventors: Gerard M. Meisel, Budd Lake, NJ 6,156,771. A 12/2000 Rubin et al. S. Arthur A. Ciociola, Far Hills, NJ FOREIGN PATENT DOCUMENTS CA 967977 5/1975 (73) Assignee: Warner-Lambert Company LLC, CA 2136164 3/1995 Morris Plains, NJ (US) CN 1092314 3/1993 CN 1118267 5/1994 (*) Notice: Subject to any disclaimer, the term of this DE 9859.499 : 12/1998 patent is extended or adjusted under 35 E. O S. A1 3.10: U.S.C. 154(b) by 234 days. FR 2244469 8/1973 FR 4506 8/1993 (21) Appl. No.: 10/196,053 FR 277 1009 11/1997 JP 56128719 3/1980 (22) Filed: Jul. 15, 2002 JP 306.6627 8/1989 O O JP 9052829 6/1995 (65) Prior Publication Data WO WO 95.01803 A1 * 1/1995 US 2004/0013741 A1 Jan. 22, 2004 WO WO 9725,979 1/1996 WO WOOO765OO 12/2000 (51) Int. Cl. WO WOO121601 3/2001 A6IF I3/00 (2006.01) ZA 61O1840 8/1993 A6F 99.6A06 3032006.O1 OTHER PUBLICATIONS A6 IK 948 (2006.01) JW Read, JL Abitbol, KD Bardhan, PJ Whorwell, B Fraitag-"Efficacy and Safety of the peripheral kappa ago (52) U.S. Cl. ....................... 424/436; 424/422; 424/430; nist fedotoZine verSuS placebo in the treatment of functional 424/433; 424/451; 424/464; 424/489 dyspepsia see comments)." Gut Nov., 1997 41(5):664-8. (58) Field of Classification Search ................. 424/422, M Delvaux, D Louvel, E Lagier, B Scherrer, JL Abitbol, J 424/430, 433,436, 451, 464, 489, 435, 439 FrexinoS-"The kappa agonist fedotoZine relieves hyper See application file for complete Search history. Sensitivity to colonic distention in patients with irritable bowel syndrome.” Gastroenetrology, Jan., 1999 (56) References Cited 116(1):38-45. U.S. PATENT DOCUMENTS HD Allescher HD, S Ahmad, M Classen, EE Daniel “Interaction of trimebutine and Jo-1196 (fedotozine) with 3,158,538 A 11/1964 Lee opioid receptors in the canine ileum.”J Pharmacol Exp Ther 3.257.275 A 6/1966 Weisberg et al. 257:836–42, May 1991. 4,301,163 A * 11/1981 Torossian et al. ........... 514/357 T. Kamiya et al., “Effects of trimebutine maleate on gastric 4,681,7554,462.982 A 7/19877/1984 SamejimaColombo etet al.al. motility- in patients with gastric ulcer,ss Journal of Gastro 5,143,728 A * 9/1992 Cappel et al. .............. 424738 enterology, vol. 33, No. 6, Dec. 1998, pp. 823–827. 5.245,080 A 9/1993 Aubard et al. J. Kountouras MD, et al., “Efficacy of Trimebutine Therapy 5,486,160 A 1/1996 Rossi et al. in Patients with Gastroesophageal Reflux Disease and Irri 5,498,422 A 3/1996 Nakamichi et al. table Bowel Syndrome', Hepato-Gastroenterology Jan. 5,516,524. A 5/1996 Kais et al. .................. 424/439 2002; vol. 49, 193-197. 5,574,054 A 11/1996 Kitagawa et al. 5,614,536 A 3/1997 Monti et al. * cited by examiner 5,656.286 A 8/1997 Miranda et al. 5,658.888 A 8/1997 Koga et al. Primary Examiner Thurman K. Page 5,686.494. A 11/1997 Asano et al. ASSistant Examiner S. Tran 5,700,4105,693,337. A 12/1997 SuzukiNakamichi et al. et al. (74) Attorney, Agent, or Firm-Linda A. Vag 5,719,197 A 2/1998 Kanios et al. (57) ABSTRACT 5,776,495 A 7/1998 Duclos et al. 5,811,547 A 9/1998 Nakamichi et al. The invention relates to compositions and methods for 5,837.285 A 11/1998 Nakamichi et al. treating and/or preventing lower gastrointestinal (GI) disor 5,919,760 A 7/1999 Simon ders in mammalian patients, more particularly for alleviating 5,980.882. A 11/1999 Eichman and/or preventing the lower GI symptoms associated with 5,981,557 A 11/1999 Nagasawa et al. Such disorders 6,024.976 A 2/2000 Miranda et al. 6,027,747 A 2/2000 Terracol et al. 6,090,412 A 7/2000 Hashimoto et al. 18 Claims, No Drawings US 6,986,901 B2 1 2 GASTRONTESTINAL COMPOSITIONS a.) an amino-ether and/or -ester oxide having the formula: This Continuation-In-Part application claims priority to R4 the utility application filed on Jul. 10, 2002 by Express Mail No EL819.32353OUS. (CH2) FIELD OF THE INVENTION The invention relates to compositions and methods for (CH2) g treating and/or preventing lower gastrointestinal (GI) disor ders in mammalian patients, more particularly for alleviating 1O and/or preventing the lower GI symptoms associated with Such disorders. in which: R is a lower alkyl, R and Rs which are the BACKGROUND OF THE INVENTION Same or different are hydrogen or lower alkyl, R is a phenyl The primary function of the gastrointestinal tract is the 15 or phenoxy nucleus optionally monoSubstituted to trisubsti absorption of ingested nutrients. This is achieved when tuted by Substituents which are identical or different, halo transit along the esophagus and gastrointestinal tract is at a gen or lower alkoxy, R is a phenyl radical optionally rate which facilitates optimal digestion and absorption of monosubstituted to trisubstituted by Substituents which are water and electrolytes. abnormal patterns in gastrointestinal the same or different, halogen, lower alkyl, lower alkoxy or motility result in number of disorders ranging from diffuse nitro, a pyridyl radical or a lower alkyl radical, Q is -O- esophageal spasm (an esophageal obstructive disorder char or -COO-, n is equal to Zero, 1 or 2, m and q are, acterized by dysphagia), achalasia (an obstructive disorder independently of one another, equal to Zero or to 1, p is an in which the lower esophageal Sphincter fails to relax integer ranging from 0 to 9; and adequately resulting in dysphagia) and noncardiac chest pain b.) a gastrointestinal active Selected from the group con to functional bowel disorders such as the irritable bowel 25 Sisting of laxatives, antidiarrheals, antibiotics, Syndrome (IBS), non-ulcer dyspepsia, and idiopathic con antiulceratives, gastric Secretion inhibitors, peristalitic Stipation. Stimulants, Serotonin (5HT) receptor antagonists, Sero IBS is particularly disturbing since it involves chronic tonin (5HT) receptor agonists, Selective Serotonin episodes of diarrhea and/or constipation for which there is reuptake inhibitor and mixtures thereof. no identifiable organic cause. The disorder appears to result Methods of treating or preventing gastrointestinal disor from faulty regulation in both the gastrointestinal and ner derS using the above compositions are also disclosed. Vous Systems. DETAILED DESCRIPTION OF THE Where drug therapy is indicated, the therapy includes prokinetic agents for constipation; anticholinergics, antis INVENTION pasmodicS Such as trimebutine, tricylic and Serotonin 35 All percentages and ratios used herein are by weight of the reuptake inhibitor antidepressants, and Sedatives for cramp total composition and all measurements made are at ing pain; and opiates (such as loperamide and 25.degree. C., unless otherwise designated. diphenoxylate) and cholestyramine for diarrhea. However, The compositions of the present invention can comprise, Such therapy has proven to have limited, if any, efficacy. consist essentially of, or consist of, the essential as well as Clearly, therefore, a significant unmet need remains for an 40 optional ingredients and components described herein. AS efficacious and comprehensive treatment of patients afflicted used herein, "consisting essentially of means that the with such lower GI disorders, including alleviation of such composition or component may include additional lower GI symptoms as chronic diarrhea, constipation and ingredients, but only if the additional ingredients do not crampS. 45 materially alter the basic and novel characteristics of the The present inventors have found that gastrointestinal claimed compositions or methods. compositions comprising a gamma-aminobutyric acid ana All publications cited herein are hereby incorporated by logs in combination with Select gastrointestinal actives pro reference in their entirety. vide a more comprehensive reduction in IBS Symptoms as AS used herein, a “pharmaceutically acceptable' compo compared to previous drug therapies. 50 nent is one that is Suitable for use with humans and/or Accordingly, an aspect of the present invention is to animals without undue adverse side effects (Such as toxicity, provide gastrointestinal compositions. irritation, and allergic response) commensurate with a rea Another aspect of the present invention is to provide Sonable benefit/risk ratio. gastrointestinal compositions which prevent, reduce or alle By “safe and effective amount” is meant an amount of a viate the symptoms associated with IBS. 55 compound or composition which is high enough to posi A further aspect of the present invention is to provide tively modify the condition being treated, but low enough to gastrointestinal compositions comprising amino-ether and/ avoid Serious Side effects at a reasonable benefit/risk ratio or ester oxides in combination with gastrointestinal actives within the Scope of Sound medical judgement. The Safe and Selected from the group consisting of laxatives, effective amount may vary with the age and physical con antidiarrheals, antibiotics, antiulceratives, gastric Secretion 60 dition of the perSon being treated, the Severity of the inhibitors, peristalitic Stimulants, Serotonin (5HT) receptor condition, the Specific ingredients employed, and like fac antagonists, Serotonin (5HT) receptor agonists, Selective torS. Serotonin reuptake inhibitor and mixtures thereof. The phrase "gastrointestinal disorder', as used herein, means a disorder of the gastrointestinal tract, including the SUMMARY OF THE INVENTION 65 Small and large intestines and the rectum, and/or Symptoms The present invention relates to compositions for treating usually attributed to a dysfunction of one or more of these or preventing gastrointestinal disorders, comprising: organs, Such as diarrhea, constipation and/or abdominal and US 6,986,901 B2 3 4 lower abdominal cramping or pain.