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 .” 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 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 7/19847/1987 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 5,693,337.5,700,410 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 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 , antidiarrheals, , Syndrome (IBS), non-ulcer dyspepsia, and idiopathic con antiulceratives, gastric Secretion inhibitors, peristalitic Stipation. , 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 and 25.degree. C., unless otherwise designated. ) 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. It is understood that Trimebutine is available under the tradenames Modulon gastro intestinal disorders include both disorders for which (Canada), Debridat (Italy), Cerekinon (Japan), and Polibutin an organic cause (e.g. infection by a parasite) is known and (Spain). A more detailed description of Fedotozine can be disorders for which no organic cause can be ascertained, found in U.S. Pat. No. 4,301,163 to Torossian et al. (1981) Such as IBS. Gastrointestinal disorders, therefore, include, and U.S. Pat. No. 5,245,080 to Aubard et al. (1993), both of but are not limited to, irritable bowel syndrome, functional which are herein incorporated by reference in their entirety. diarrhea, ulcerative colitis, collagenous colitis, microscopic FedotoZine has been administered effectively at dosages colitis, lymphocytic colitis, inflammatory bowel disease, of up to 210 mg daily, preferably 30 to 70 mg three times Crohn's disease, and infectious diarrhea Such as diarrhea daily, and up to 100 mg intravenously daily. Trimebutine has asSociated with amebiasis, giardiasis, a viral infection, cytomegalovirus infection, or a pathogenic bacterial infec been effectively administered orally at up to 600 mg/day, tion. The bacterial infection may, for example, be an infec preferably up to 200 milligrams 3 times daily, or tion by a bacterium Selected from the group consisting of a intramuscularly/intravenously at up to 100 milligrams every bacterium of the genus Escherichia, an Escherichia coli 12 hours. While mindful of individual patient parameters O157:H7 bacterium, a bacterium of the genus Salmonella, a and Symptom Severity, the amino-ether and/or ester oxides bacterium of the genus Shigella, a bacterium of the genus 15 are preferably administered orally at 1-75 mg/kg, preferably Campylobacter, a bacterium of the Species Campylobacter 2-50 mg/kg and most preferably at 5-20 mg/kg. jejuni, and a bacterium of the genus Yersinia Gastrointestinal Actives The gastrointestinal compositions of the present The compositions also comprise a Safe and effective invention, including the essential and optional components amount of a gastrointestinal active. In one embodiement the thereof, are described in detail hereinafter. gastrointestinal active is Selected from the group consisting ESSential Ingredients of laxatives, antidiarrheals, antibiotics, antiulceratives, gas Amino-Ether and/or Ester Oxides tric Secretion inhibitors, peristalitic stimulants, (5HT) recep The compositions and methods of the present invention tor antagonists, Serotonin (5HT) receptor agonists, selective comprise a safe and effective amount of an amino-ether Serotonin reuptake inhibitors and mixtures thereof. and/or -ester oxide. Amino-ether and/or -ester oxides 25 Suitable gastrointestinal actives include, but are not lim according to the invention conform to the formula: ited to, the following: Laxatives A Safe and effective amount of a may be added to R4 the compositions of the Subject invention. The exact amount (CH2) of laxative to be used in the compositions will depend on the particular laxative utilized since Such agents vary widely in R- C- (CH2)n-Q o (CH2) R5 potency. A more complete description of the various (CH2) g laxatives, including acceptable laxative effective amounts thereof for use in unit dose compositions of the present 35 invention can be found in U.S. Pat. No. 5,516,524; herein incorporated by reference in its entirety, as well as the Handbook of Nonprescription Drugs, 12th Ed., Chapter 12, in which: R is a lower alkyl, R and Rs which are the same pp. 279-290 (American Pharmaceutical Association, or different are hydrogen or lower alkyl, R is a phenyl or Washington, D.C.; 2000); and Drug Facts and Comparisons phenoxy nucleus optionally monoSubstituted to trisubsti 40 (54th Ed. 2000), pp. 1166-1177; the cited pages of which are tuted by Substituents which are identical or different, halo herein incorporated by reference. gen or lower alkoxy, Rs is a phenyl radical optionally Laxatives useful herein include, but are not limited to, monosubstituted to trisubstituted by Substituents which are the same or different, halogen, lower alkyl, lower alkoxy or hydrophilic derivatives of cellulose (such methylcellulose nitro, a pyridyl radical or a lower alkyl radical, Q is -O- and carboxymethylcellulose ), malt Soup extract, or -COO-, n is equal to Zero, 1 or 2, m and q are, 45 polyacrylic resins (preferably hydrophilic forms Such as independently of one another, equal to Zero or to 1, p is an polycarbophil and polycarbophil), plantago Seeds, integer ranging from 0 to 9. husk, dioctyl calcium SulfoSuccinate, dioctyl potas By lower radical are meant radicals having from 1 to 10 sium SulfoSuccinate, dioctyl Sodium SulfoSuccinate, mineral carbon atoms, preferably 1 to 6 carbon atoms, especially 1 oil, citrate, , magnesium to 4 carbon atoms in a Straight or branched chain. 50 Sulfate, dibasic Sodium phosphate, monobasic Sodium If R is alkyl, it is preferably methyl. If the amino-ether phosphate, Sodium biphosphate, glycerin, anthraquinones or oxides are halogenated, they are preferably brominated or anthracene laxatives (such as aloe, cascara Sagrada, chlorinated. danthron, Senna, aloin, casanthranol, frangula, and rhubarb), The invention also embraces the acid addition salts of diphenylmethanes (such as and ), amino-ether oxides, notably those of mineral acids, Such as 55 and . Mixtures of the above laxatives can also be halohydrates, Sulphates, phosphates, or organic acids Such as used. maleates, citrates, malates, tartrates, methaneSulphonates, Antidiarrheals camphoSulphonates, benzoates, etc. A Safe and effective amount of an antidiarrheal may be The invention further covers both racemic and optionally added to the compositions of the subject invention. The active forms which can be separated, particularly by forming 60 exact amount of the antidiarrheal to be used in the compo Salts with optically active acids. Sitions will depend on the particular antidiarrheal utilized Examples of Suitable amino-ether and/or -ester oxides Since Such agents vary widely in potency. A more complete include trimebutine (3,4,5-trimethoxybenzoic acid description of the various antidiarrheals, including accept 2-(dimethylamino)-2-phenylbutyl ester), fedotozine ((R)-O- able antidiarrheal effective amounts thereof for use in unit ethyl-N,N-dimethyl-O-(3,4,5-trimethoxyphenyl) 65 dose compositions of the present invention can be found in methoxymethyl benene methanamine) and mixtures the Handbook of Nonprescription Drugs, 12th Ed., Chapter thereof. 13, pp. 312-316 (American Pharmaceutical ASSociation, US 6,986,901 B2 S 6 Washington, D.C.; 2000); and Drug Facts and Comparisons of gastric Secretion inhibitors to be used in the compositions (54th Ed. 2000), pp. 1178–1182; the cited pages of which are will depend on the particular gastric Secretion inhibitor herein incorporated by reference. utilized Since Such agents vary widely in potency. A more Antidiarrheals useful herein include, but are not limited complete description of the various Gastric Secretion to, natural or Synthetic opiates (such as , Inhibitors, including acceptable e Gastric Secretion Inhibitor diphenoxylate, pargoric, opium tincture, and loperamide), effective amounts thereof for use in unit dose compositions anticholinergics (such as belladonna alkoloids-atropine of the present invention can be found in the Drug Facts and hyoscyamine, and hyosine), acetyltannic acid, albumin Comparisons (54th Ed. 2000), pp. 352-354; the cited pages tannate, alkofanone, aluminum Salicylates, catechin, of which are herein incorporated by reference. Mixtures of lidamidine, mebiquine, trillium, and uZarin. Mixtures of the the above gastric Secretion inhibitors can also be used. above antidiarrheals can also be used. Peristaltic Stimulants Antiulcerative A Safe and effective amount of a peristaltic may A Safe and effective amount of an antiulcerative may be be added to the compositions of the Subject invention. added to the compositions of the subject invention. The Suitable peristaltic Stimulants include, but are not limited to, exact amount of the antiulcerative to be used in the com 15 deXpanthenol, metoclopromide, cisapride, and domperi positions will depend on the particular antiulcerative utilized done. The exact amount of peristalitic Stimulants to be used Since Such agents vary widely in potency. A more complete in the compositions will depend on the particular peristalitic description of the various antiulceratives, including accept Stimulant utilized since Such agents vary widely in potency. able antiulcerative effective amounts thereof for use in unit A more complete description of the various, Peristaltic dose compositions of the present invention can be found in Stimulants including acceptable Peristaltic Stimulant effec the Drug Facts and Comparisons (54th Ed. 2000), pp. tive amounts thereof for use in unit dose compositions of the 1131-1139; the cited pages of which are herein incorporated present invention can be found in the Drug Facts and by reference. Comparisons (54th Ed. 2000), pp. 1188–1193; the cited Antiulcerative useful in the present invention include, but pages of which are herein incorporated by reference. Mix are not limited to, aluminum complex, 25 tures of the above peristalitic Stimulants can also be used. e-acetamidocaproic acid Salt, , arbaprostil, benexate hydrochloride, sol (dried), Serotonin (5HT.) Receptor Antagonist , , , , eSaprazole, A Safe and effective amount of a Serotonin (5HT) recep , ftaxilide, , guaiaZulene, irSogladine, tor antagonist may be added to the compositions of the , , ornoprostil, Y-ory Zanol, pifarnine, subject invention. Suitable serotonin (5HT) receptor , plaunotol, , rioprostil, rosaprostol, antagonists include, but are not limited to, cilansetron, rotraxate, , , Spizofurone, dolasetron, Ondansetron, aloSetron and mixtures thereof. The , , trimoprostil, thrithiozine, , exact amount of Serotonin (5HT) receptor antagonists to be and . Mixtures of the above antiulcerative can used in the compositions will depend on the particular also be used. 35 Serotonin (5HT) receptor antagonist utilized since Such Antibiotics agents vary widely in potency. A more complete description A Safe and effective amount of an may be of the various Serotonin (5HT) receptor antagonists, includ added. The exact amount of antibiotic to be used in the ing acceptable effective amounts thereof for use in unit dose compositions will depend on the particular antibiotic utilized compositions of the present invention can be found in U.S. Since Such agents vary widely in potency. 40 Pat. No. 6,235,745, herein incorporated by reference and the A wide variety of antibiotics may be used according to the Drug Facts and Comparisons (54th Ed. 2000), pp. 869-872 invention, including for example nitroimidazole antibiotics and KU47; the cited pages of which are herein incorporated (e.g. tinidazole or metronidazole), tetracyclines (e.g. by reference. Mixtures of the above serotonin (5HT) recep tetracyclin, doxycyclin and minocyclin), pencillins (e.g. tor antagonists can also be used. amoxycillin, amplicillin and meZlocillin), cephalosporins 45 Serotonin (5HT.) Receptor Agonist (e.g. cefachlor, cefadroxil, cephradine, cefuroxime, A Safe and effective amount of a Serotonin (5HT) recep cefuroxime axetil, cephalexin, cefpodoxime proxetil, tor agonist may be added to the compositions of the Subject ceftazidime and ceftriaxone), carbopenems (e.g. imipenem invention. Suitable Serotonin (5HT) receptor agonists and meropenem), amino-glycosides (e.g. paromonycin), include, but are not limited to , renZapride and macrollide antibiotics (e.g. erythromycin, clarithromycin and 50 . The exact amount of Serotonin (5HT) recep azithromycin), lincosamide antibiotics (e.g. clindamycin), tor agonists to be used in the compositions will depend on 4-quinolones (e.g. ofloxacin, ciprofloxacin, pefloxacin and the particular Serotonin (5HT) receptor agonist utilized norfloxacin), rifamycins (e.g. rifampicin), nitrofurantoin and Since Such agents vary widely in potency. Tegaserod is a derivatives of 10-(1-hydroxyethyl)-11-oxo-1-azatricyclo partial Serotonin (5HT) receptor agonist which accelerates 7.2.0.0.3.8 undec-2-ene-2-carboxylic acid and mixtures 55 Orocecal transit (without effect on gastic emptying) and thereofas well as those described in U.S. Pat. No. 5,719, 197 tends to enhance colonic transit. 12 mg/day of tegaserod is to Kanios et al. (1998), published European Patent Specifi taught to result in effective relief of irritable bowel syndrome cation No. 0416953 and published International Patent symptoms. Prucalopride is a full serotonin (5HT) receptor Specification No. WO92/03437, each of which are herein agonist which accelerates gastric, Small bowel and colonic incorporated by reference in its entirety. 60 transit in functional constipation. Up to 4 mg/day, particu Mixtures of any of the above-mentioned antibiotic com larly 2–4 mg/day, of prucalopride is taught to result in pounds can also be used. effective relief of untoward bowel symptoms. Renzapride Gastric Secretion Inhibitors possesses both Serotonin (5HT) receptor agonist and Sero A Safe and effective amount of a gastric Secretion inhibitor tonin (5HT) receptor antagonist activity, providing may be added to the compositions of the Subject invention. 65 increased gastric emptying and reduced gastrintestinal tran Suitable gastric Secretion inhibitors include, but are not sit time. Mixtures of the above serotonin (5HT) receptor limited to, enterogastrone and . The exact amount agonists can also be used. US 6,986,901 B2 7 8 Selective Serotonin Reuptake Inhibitors A Safe and effective amount of a Selective Serotonin -continued reuptake inhibitor may be added to the compositions of the Subject invention. Suitable Selective Serotonin reuptake Suitable Strengths and inhibitors include, but are not limited to, fluoxetine, Dosage Forms (Brand fluvoxamine, paroxetine, and Sertraline. The exact amount Generic Name Names) Usual Adult Dosage of Selective Serotonin reuptake inhibitors to be used in the Selective Serotonin compositions will depend on the particular Selective Sero Reuptake Inhibitors tonin reuptake inhibitor utilized since Such agents vary Fluoxetine 20-mg capsules; 20 widely in potency. A more complete description of the mg/5 mL oral solution various Selective Serotonin reuptake inhibitors, including (Prozac) acceptable effective amounts thereof for use in unit dose Fluvoxamine 50-, 100-mg tablets compositions of the present invention can be found in the (Luvox) Paroxetine 10 mg/5 mL oral Drug Facts and Comparisons (54th Ed. 2000), pp. 918-928; suspension; 10-, 20-, the cited pages of which are herein incorporated by refer 15 30-, 40-mg tablets ence. Mixtures of the above Selective Serotonin reuptake (Paxil) inhibitors can also be used. Sertraline 25-, 50-, 100-mg tablets (Zoloft) Preferred for use herein as the gastrointestinal active are Serotonin (5HT) bulk forming laxatives Such as methylcellulose, carboxym Receptor Antagonist ethylcellulose Sodium, malt Soup extract, hydrophilic poly Alosetron 1-mg tablets (Lotronex) 1 mg twice daily acrylic resins, plantago Seeds, psyllium husk and mixtures Granisetron 1-mg tablets (Kytril) thereof. Most preferred for use herein are hydrophilic poly Ondansetron 4-, 8-mg tablets 4 mg three times daily acrylic resins Such as polycarbophil and/or calcium poly (Zofran) carbophil. Calcium polycarbophil is monographed and every Gastric Secretion Inhibitors unit contains 500 mg of polycarbophil (650 mg 25 polycarbophil) with a dosing of 2 units(1 gm polycarbophil) Octreotide 50, 100, 200, 500, 1000 up to 4 times a day and, preferably not to exceed 12 units (6 pig?mL sterile solution gm) in a 24 hour period. for s.c. or i.v. injection Further dosage information concerning disclosed actives is (Sandostatin); 10-, 20-, 30-mg sterile Summarized in the table below: suspension for i.m. injection (Sandostatin LAR Depot) Suitable Strengths and CNS = central nervous system; GI = gastrointestinal; 5-HT3 = serotonin Dosage Forms (Brand (5-hydroxytryptamine) receptor subtype 3; i.m. = intramuscular; i.v. = Generic Name Names) Usual Adult Dosage 35 intravenous; s.c. = subcutaneous. Bulk-Foaming Laxatives Optional Ingredients Calcium polycarbophil 625-mg tablets that 1-6 g/day as poly A Safe and effective amount of an anti-inflammatory agent provide 500 mg of carbophil in divided may be added to the compositions of the Subject invention. polycarbophil doses 40 (Konsyl Fiber) The exact amount of anti-inflammatory agent to be used in Methylcellulose 2 g/Tbsp oral powder 4-6 g/day in divided the compositions will depend on the particular anti (Citrucel) doses inflammatory agent utilized since Such agents vary widely in Psyllium 3.4 g/tsp or 3.4 g/Tbsp 2.5-30 g/day in potency. A more complete description of the various oral powder, 1.7 g wafer divided doses (Metamucil) 45 NSAID's, including acceptable analgesically effective Antidiarrheals (opiate amounts thereof for use in unit dose compositions of the and anticholinergic present invention also appears in applicants co-pending U.S. agents) application Ser. No. 474,358, filed Mar. 11, 1983, and now Diphenoxylate 2.5-mg tablets; 2.5 2.5-5 mg four times U.S. Pat. No. 4,486,436, and Ser. No. 578,288, filed Feb. 8, mg/5 mL oral liquid daily as needed for 50 1984, now U.S. Pat. No. 4,522,826 the entire disclosures of (Lomotil) diarrhea which are incorporated herein by reference. Loperamide 2-mg tablets and 2-4 mg up to four capsules; 1 mg/5 mL times daily as needed. Steroidal anti-inflammatory agents, including but not lim oral liquid (Imodium) ited to, cortico Steroids Such as , Dicyclomine 10-mg capsules; 20-mg 10–20 mg three or hydroxyltriamcinolone, alpha-methyl , tablets; 10 mg/5 mL four times daily 55 dexamethasone-phosphate, beclomethasone dipropionates, syrup (Bentyl) Hyoscyamine 0.125-mg tablets; 0.125 0.15-0.3 mg up to Valerate, , desoxymethasone, desoxycor mg/mL, 0.125 mg/5 four times daily ticosterone acetate, dexamethasone, , diflo mL elixir (Levsin) rasone diacetate, Valerate, fluadrenolone, flu Tincture of bellonna Tincture with 0.3 0.6-1 mL three or four clorolone acetonide, , flumethasone pivalate, mg/mL alkaloids of times daily belladonna leaf 60 fluosinolone acetonide, , flucortine butylesters, Peristaltic Stimulants , (fluprednylidene) acetate, flurandrenolone, , hydrocortisone acetate, hydro Cisapride 10-, 20-mg tablets: 5 5-10 mg three times butyrate, , mg/mL oral suspension daily (Propulsid) acetonide, cortisone, corto doxone, flucetonide, Metoclopramide 5-, 10-mg tablets; 5 65 fluidrocortisone, difluoroSone diacetate, fluradrenolone, mg/5 mL oral liquid fluidrocortisone, difluroSone diacetate, fluradrenolone acetonide, , amcinafel, , betametha US 6,986,901 B2 10 Sone and the balance of its esters, , chlor rhizic acid, and derivatives thereof (e.g., Salts and esters). acetate, clocortelone, cleScinolone, dichlorisone, Suitable Salts of the foregoing compounds include metal and diflurprednate, flucloronide, , fluoromethalone, ammonium Salts. Suitable esters include C-C Saturated or , , hydrocortisone Valerate, unsaturated esters of the acids, preferably Co-C, more hydrocortisone cyclopentylpropionate, , preferably C-C. Specific examples of the foregoing , , , prednisone, include oil Soluble licorice extract, the glycyrrhizic and beclomethasone dipropionate, triamcinolone, and mixtures glycyrrhetic acids themselves, monoammonium thereof may be used. Mixtures of the above steroidal anti glycyrrhizinate, monopotassium glycyrrhizinate, dipotas inflammatory agents can also be used. The preferred Steroi sium glycyrrhizinate, 1-beta-glycyrrhetic acid, Stearyl dal anti-inflammatory for use is hydrocortisone. glycyrrhetinate, and 3-Stearyloxy-glycyrrhetinic acid, and A Second class of anti-inflammatory agents which is disodium 3-Succinyloxy-beta-glycyrrhetinate. Stearyl gly useful in the compositions includes the nonsteroidal anti cyrrhetinate is preferred. inflammatory agents. The variety of compounds encom Mixtures of any of the above anti-inflammatory agents passed by this group are well-known to those skilled in the can also be used. art. For detailed disclosure of the chemical Structure, 15 Carriers Synthesis, Side effects, etc. of non-Steroidal anti In accordance with the practices of the present invention, inflammatory agents, reference may be had to Standard texts, the gastrointestinal compositions may be administered in including Anti-inflammatory and Anti-Rheumatic Drugs, K. admixture with Suitable pharmaceutical diluents, carriers or D. Rainsford, Vol. I-III, CRC Press, Boca Raton, (1985), other excipients (collectively referred to as “carrier” and Anti-inflammatory Agents, Chemistry and Pharmacol materials) Suitably selected with respect to the intended ogy 1, R. A. Scherrer, et al., Academic Press, New York route of administration and conventional pharmaceutical (1974), each incorporated herein by reference. practices. The gastrointestinal compositions of the present Specific non-Steroidal anti-inflammatory agents useful in invention are typically mixed with a pharmaceutically the composition invention include, but are not limited to: acceptable carrier. This carrier can be a Solid or liquid and 25 the type is generally chosen based on the type of adminis 1) the oxicams, Such as piroxicam, iSoxicam, tenoxicam, tration being used. Sudoxicam, and CP-14304; The actives can be coadministered in the form of a tablet 2) the Salicylates, Such as aspirin, disalcid, benorylate, or capsule, liposome, as an agglomerated powder or in a trilisate, Safapryn, Solprin, diflunisal, and fendosal; liquid form. Capsule or tablets can be easily formulated and 3) the acetic acid derivatives, Such as diclofenac, can be made easy to Swallow or chew; other Solid forms fenclofenac, indomethacin, Sulindac, tolmetin, include granules, and bulk powders. Tablets may contain isoXepac, furofenac, tiopinac, Zidometacin, acematacin, Suitable binders, lubricants, diluents, disintegrating agents, fentiaZac, Zomepirac, clindanac, OXepinac, felbinac, coloring agents, flavoring agents, flow-inducing agents, and and ketorolac, melting agents. Examples of Suitable liquid dosage forms 4) the fenamates, Such as mefenamic, meclofenamic, 35 include Solutions or Suspensions in water, pharmaceutically flufenamic, niflumic, and tolfenamic acids, acceptable fats and oils, alcohols or other organic Solvents, 5) the propionic acid derivatives, Such as ibuprofen, including esters, emulsions, Syrups or elixirs, Suspensions, naproxen, benoxaprofen, flurbiprofen, ketoprofen, Solutions and/or Suspensions reconstituted from non fenoprofen, fenbufen, indopropfen, pirprofen, effervescent granules and effervescent preparations recon carprofen, oxaprozin, pranoprofen, miroprofen, 40 Stituted from effervescent granules. Such liquid dosage tioxaprofen, Suprofen, alminoprofen, and tiaprofenic; forms may contain, for example, Suitable Solvents, and preservatives, emulsifying agents, Suspending agents, 6) the pyrazole S, Such as phenylbuta Zone, diluents, Sweeteners, thickeners, and melting agents. Oral OxyphenbutaZone, feprazone, azapropaZone, and tri dosage forms optionally contain flavorants and coloring methaZone. 45 agents. Mixtures of these non-Steroidal anti-inflammatory agents Examples of Suitable tablet or capsule form ingredients, may also be employed, as well as the pharmologically include but are not limited, to oral non-toxic pharmaceuti acceptable Salts and esters of these agents. For example, cally acceptable inert carrier Such as lactose, Starch, Sucrose, etofenamate, a derivative, is particularly cellulose, magnesium Stearate, dicalcium phosphate, cal useful for topical application. Of the nonsteroidal anti 50 cium Sulfate, and the like. Moreover, when desired inflammatory agents, ibuprofen, naproxen, flufenamic acid, or necessary, Suitable binders, lubricants, disintegrating etofenamate, aspirin, mefenamic acid, meclofenamic acid, agents and coloring agents can also be incorporated in the piroXicam and felbinac are preferred; ibuprofen, naproxen, mixture. Suitable binders include Starch, gelatin, natural etofenamate, aspirin and flufenamic acid are most preferred. Sugars, corn Sweeteners, natural and Synthetic gums Such as Finally, So-called “natural anti-inflammatory agents are 55 acacia, Sodium alginate, carboxymethylcellulose, polyethyl useful in methods of the Subject invention. Such agents may ene glycol and waxes. Among the lubricants there may be Suitably be obtained as an extract by Suitable physical and/or mentioned for use in these dosage forms, boric acid, chemical isolation from natural Sources (e.g., plants, fungi, Sodiumbenzoate, Sodium acetate, Sodium chloride, etc. Dis by-products of microorganisms). For example, candelilla integrators include, without limitation, Starch, wax, alpha bisabolol, aloe Vera, Manjistha (extracted from 60 methylcellulose, agar, bentonite, guar gum, etc. plants in the genus Rubia, particularly Rubia Cordifolia), Of course, additionally, the compositions of the present and Guggal (extracted from plants in the genus invention may be formulated in Sustained release form to Commiphora, particularly Commiphora Mukul), kola provide the rate controlled release of any one or more of the extract, chamomile, and Sea whip extract, may be used. components to optimize the therapeutic effects, i.e., Additional anti-inflammatory agents useful herein include 65 analgesia, Skeletal muscle relaxation, etc. while minimizing compounds of the Licorice (the plant genus/species Glycyr undesirable Side effects. Suitable dosage forms for Sustained rhiza glabra) family, including glycyrrhetic acid, glycyr release include layered tablets containing layers of varying US 6,986,901 B2 11 12 disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing Such impregnated or encapsulated porous polymeric matrices. Ingredient %fwfw Similarly, injectable dosage units may be utilized to Loperamide O.SOO accomplish intravenous, intramuscular or Subcutaneous Trimebutine SO.OOO Corn Starch 27.OOO administration and, for Such parenteral administration, Suit USP1 able Sterile aqueous or non-aqueous Solutions or USP2 7.5 Suspensions, optionally containing appropriate Solutes to Lactose 15.OOO effectuate isotonicity, will be employed. 1O Monohydrate Specific examples of pharmaceutical acceptable carriers NF3 and excipients that may be used to formulate oral dosage "Corn Starch Modified supplied by National Starch and Chemical Co. forms of the present invention are described in U.S. Pat. No. *Supplied by Whittaker, Clark & Daniels, Inc. 3,903,297 to Robert, issued Sep. 2, 1975, herein incorpo Supplied by Archer Daniel Midland Co. rated by reference in its entirety. Techniques and composi 15 tions for making dosage forms useful in the present inven Once mixed the ingredients are incoporated into #2 hard tion are described in the following references: 7 Modern gelatin capsules composed of gelatin, titanium dioxide and Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, colorant and administered orally. Editors, 1979); Example II Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage The following is an example of a Trimebutine-laxative Forms 2nd Edition (1976), each of which are herein incor combination capsule composition of the present invention. porated by reference in its entirety. The capsule is formed by combining and mixing the ingre The gastrointestinal compositions of the present invention dients of each column using conventional technology and may also be formulated and administered by other methods 25 transferring the mixture to an appropriate sized hard gelatin known for administering gastrointestinal actives. For capsule for oral administration. example, the composition may be adapted for topical admin istration in the form of rectal preparations Such as a rectal cream, gel, ointment, or Suppository. Ingredient %fwfw Method of Treatment The method of treatment can be any suitable method Trimebutine 25.OOO Calcium SO.OOO which is effective in the treatment of the particular type of Polycarbophil lower gastrointestinal disorder that is being treated. Treat Microcrystalline 7.5 ment may be oral, rectal, parenteral, intravenous adminis Cellulose NF tration or injection. The method of applying an effective 35 Tale USP2 6.25.OOO amount also varies depending on the lower gastrointestinal "Available as Avicel 102 supplied by FMC Corporation disorder being treated. It is believed that oral treatment by *Supplied by Whittaker, Clark & Daniels, Inc. tablet, capsule or liquid will be the preferred method of administering the compounds to warm blooded mammals. Once mixed the ingredients are incoporated into #2 hard The method of treating lower gastrointestinal disorders 40 gelatin capsules composed of gelatin, titanium dioxide and may also be by rectal, parenteral, or intravenous adminis colorant and administered orally. tration. The actual time and dosage will depend on the type of the lower gastrointestinal disorder being treated and the Example III desired blood levels. The following is an example of an antiulcerative tablet 45 composition of the present invention. EXAMPLES The compositions in the following illustrate Specific embodiments of the gastrointestinal compositions of the Ingredient %fwfw present invention, but are not intended to be limiting thereof. 50 Trimebutine 40.OOO Other modifications can be undertaken by the skilled artisan Ranitidine HCL 3O.OOO without departing from the Spirit and Scope of this invention. Microcrystalline 24.40 All exemplified compositions can be prepared by conven Cellulose Lactose 4.OOO tional formulation and mixing techniques. Component Monohydrate amounts are listed as weight percents and exclude minor 55 materials. Such as diluents, filler, and so forth. The listed Magnesium 1.60 formulations, therefore, comprise the listed components and Stearate NF any minor materials associated with Such components. "Available as Avicel 102 supplied by FMC Corporation *Supplied by Archer Daniel Midland Co. Example I 60 Magnesium Stearate (Light) supplied by Witco Corporation. The following is an example of an antidiarrheal capsule In a Suitable vessel, the trimebutine, ranitidine HCL, composition of the present invention. The capsule is formed microcrystalline cellulose and lactuose monohydrate are by combining and mixing the ingredients of each column milled to a Suitable size and mixed until homogeneous. The using conventional technology and transferring the mixture 65 magnesium Strearate is added and the mixture is mixed until to an appropriate sized hard gelatin capsule for oral admin homogeneous. The mixture is then discharged and com istration. pressed using conventional tablet tooling to a Suitable hard US 6,986,901 B2 13 14 ness (e.g., 10-12 kp) to target a net table weight of 500 mg. gefarnate, guaiaZulene, irSogladine, nizatidine, omeprazole, The tablet is administered orally. omoproStil, Y-ory Zanol, pifarnine, pirenzepine, plaunotol, What is claimed is: ranitidine, rioprostil, rosaprostol, rotraxate, roXatidine 1. A composition for treating or gastrointestinal disorders, acetate, Sofalcone, Spizofurone, Sucralfate, teprenone, comprising: 5 trimoprostil, thrithiozine, troXipide, Zolimidine and mixtures a.) a safe and effective amount of an amino-ether and/or thereof. -ester oxide having the formula: 5. A composition according to claim 1, wherein the gastric Secretion inhibitor is Selected from the group consisting of R4 enterogastrone, octreotide and mixtures thereof. (CH2) 6. A composition according to claim 1, wherein the peristalitic Stimulant is Selected from the group consisting of metoclopromide, cisapride, domperidone and mixtures (CH2) g thereof. 15 7. A composition according to claim 1, wherein the Serotonin (5HT) receptor antagonist is selected from the group consisting of renZapride cilansetron, Ondansetron, alosetron and mixtures thereof. in which: R is a lower alkyl, R and R which are the 8. A composition according to claim 1, wherein the Same or different are hydrogen or lower alkyl, R is a Serotonin (5HT) receptor agonist is selected from the group phenyl or phenoxy nucleus optionally monoSubstituted consisting of tegaserod, prucalopride and mixtures thereof. to trisubstituted by Substituents which are identical or 9. A composition according to claim 1, wherein the different, halogen or lower alkoxy, R is a phenyl Selective Serotonin reuptake inhibitor is Selected from the radical optionally monosubstituted to trisubstituted by group consisting of fluoxetine, fluvoxamine, paroxetine, Substituents which are the same or different, halogen, 25 Sertraline and mixtures thereof. lower alkyl, lower alkoxy or nitro, a pyridyl radical or 10. A composition according to claim 1, wherein antibi a lower alkyl radical, Q is -O- or -COO-, n is otic is Selected from the group consisting of nitroimidazole equal to Zero 1 or 2, m and q are, independently of one antibiotics, tetracyclines, pencillins, cephalosporins, another, equal to Zero or to 1, wherein the amino-ether carbopenems, amino-glycosides, macrollide antibiotics, lin and/or -ester oxide is Selected from the group consist cosamide antibiotics, 4-quinolones, rifamycins, ing of trimebutine, fedotoZine and mixtures thereof; toin and derivatives of 10-(1-hydroxyethyl)-11-oxo-1- and azatricyclo7.2.0.0.3.8 undec-2-ene-2-carboxylic acid and b.) a safe and effective amount of a gastrointestinal active mixtures thereof. Selected from the group consisting of laxatives, 11. A composition according to claim 1, wherein the antidiarrheals, antibiotics, antiulceratives, gastric 35 antiinflammatory compound is Selected from the group Secretion inhibitors, peristalitic Stimulants, Serotonin consisting of , non-Steroidal antiinflammatory (5HT) receptor antagonists, Serotonin (5HT) receptor compounds and mixtures thereof. agonists, Selective Serotonin reuptake inhibitor and 12. A composition according to claim 11, wherein the mixture thereof; and antiinflammatory compound is a non-Steroidal antiinflam c.) an anti-inflammatory compound. 40 matory compound. 2. A composition according to claim 1, wherein the 13. A composition according to claim 1, in the form of a laxative is Selected from the group consisting of tablet, capsule, microcapsule, Suspension, Solution, methylcellulose, carboxymethylcellulose Sodium, malt Soup injectable, rectal Suppository, rectal cream, rectal ointment, extract, polyacrylic resin, plantago Seeds, dioctyl calcium rectal gel. SulfoSuccinate, dioctyl potassium SulfoSuccinate, dioctyl 45 14. A composition according to claim 1, wherein the Sodium SulfoSuccinate, , , mag gastrointestinal active is a laxative. nesium hydroxide, , dibasic Sodium 15. A composition according to claim 1, wherein the phosphate, monobasic Sodium phosphate, Sodium laxative is a bulk forming laxative. biphosphate, glycerin, anthraquinones, diphenylmethanes, 16. A composition according to claim 1, wherein the castor oil and mixtures thereof. 50 laxative is Selected from the group consisting of 3. A composition according to claim 1, wherein the polycarbophil, calcium polycarbophil and mixtures thereof. antidiarrheal is Selected from the group consisting of natural 17. A composition for treating or gastrointestinal disor opiates, Synthetic opiates, anticholinergics, acetyltannic derS according claim 1, comprising: acid, albumin tannate, alkofanone, aluminum Salicylates, a.) a safe and effective amount of trimebutine, and catechin, lidamidine, mebiquine, trillium, uZarin and mix 55 tures thereof. b.) a safe and effective amount of polycarbophil. 4. A composition according to claim 1, wherein the 18. A composition for treating or gastrointestinal disor antiulcerative is Selected from the group consisting of ace derS according claim 1, comprising: glutamide aluminum complex, e-acetamidocaproic acid Zinc a.) a safe and effective amount of fedotozine; and Salt, acetoxolone, arbaprostil, benexate hydrochloride, bis 60 c.) a safe and effective amount of polycarbophil. muth Subcitrate Sol (dried), carbenoxolone, cetraxate, cimetidine, enprostil, esaprazole, famotidine, ftaXilide, k k k k k