sign in sign up
<<
Home , Acetoxolone, Carbenoxolone, Zolimidine

US 20040013741A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0013741 A1 Meisel et al. (43) Pub. Date: Jan. 22, 2004

(54) GASTROINTESTINAL COMPOSITIONS Publication Classification (51) Int. Cl." ...... A61K 38/39; A61K 35/78; (76) Inventors: Gerard M. Meisel, Budd Lake, NJ A61K 33/06; A61K 33/08; (US); Arthur A. Ciociola, Far Hills, NJ A61K 31/12: A01N 33/02 (US) (52) U.S. Cl...... 424/601; 424/692; 424/697; 424/731; 424/738; 424/750; 514/57; 514/23: 514/574; 514/540; Correspondence Address: 514/357; 514/651; 514/547; Warner-Lambert Company 514/680; 514/161; 514/282; 201 Tabor Road 514/2; 514/762 Morris Plains, NJ 07950 (US) (57) ABSTRACT The invention relates to compositions and methods for (21) Appl. No.: 10/196,053 treating and/or preventing lower gastrointestinal (GI) disor ders in mammalian patients, more particularly for alleviating and/or preventing the lower GI symptoms associated with (22) Filed: Jul. 15, 2002 Such disorders. US 2004/0013741 A1 Jan. 22, 2004

GASTRONTESTINAL COMPOSITIONS antagonists, Serotonin (5HT) receptor agonists, Selective 0001. This Continuation-In-Part application claims pri Serotonin reuptake inhibitor and mixtures thereof. ority to the utility application filed on Jul. 10, 2002 by SUMMARY OF THE INVENTION Express Mail No. EL819323530US. 0011. The present invention relates to compositions for FIELD OF THE INVENTION treating or preventing gastrointestinal disorders, comprising: 0002 The invention relates to compositions and methods 0012 a.) an amino-ether and/or -ester oxide having for treating and/or preventing lower gastrointestinal (GI) the formula: disorders in mammalian patients, more particularly for alle viating and/or preventing the lower GI symptoms associated with Such disorders. R4 (CH2) BACKGROUND OF THE INVENTION 0003. The primary function of the gastrointestinal tract is the absorption of ingested nutrients. This is achieved when (CH2) g transit along the esophagus and gastrointestinal tract is at a rate which facilitates optimal digestion and absorption of water and electrolytes. abnormal patterns in gastrointestinal motility result in number of disorders ranging from diffuse esophageal spasm (an esophageal obstructive disorder char 0013 in which: R is a lower alkyl, R and Rs which are acterized by dysphagia), achalasia (an obstructive disorder the same or different are hydrogen or lower alkyl, R is a in which the lower esophageal Sphincter fails to relax phenyl or phenoxy nucleus optionally monoSubstituted to adequately resulting in dysphagia) and noncardiac chest pain trisubstituted by Substituents which are identical or different, to functional bowel disorders such as the irritable bowel halogen or lower alkoxy, Rs is a phenyl radical optionally Syndrome (IBS), non-ulcer dyspepsia, and idiopathic con monosubstituted to trisubstituted by Substituents which are Stipation. the same or different, halogen, lower alkyl, lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical, Q is -O- 0004 IBS is particularly disturbing since it involves or -COO-, n is equal to Zero, 1 or 2, m and q are, chronic episodes of diarrhea and/or constipation for which independently of one another, equal to zero or to 1, p is an there is no identifiable organic cause. The disorder appears integer ranging from 0 to 9; and to result from faulty regulation in both the gastrointestinal and nervous Systems. 0014) b.) a gastrointestinal active selected from the group consisting of laxatives, antidiarrheals, antibi 0005. Where drug therapy is indicated, the therapy otics, antiulceratives, gastric Secretion inhibitors, includes prokinetic agents for constipation; anticholinergics, peristalitic stimulants, Serotonin (5HT) receptor antispasmodicS Such as trimebutine, tricylic and Serotonin antagonists, Serotonin (5HT) receptor agonists, reuptake inhibitor antidepressants, and Sedatives for cramp Selective Serotonin reuptake inhibitor and mixtures ing pain; and opiates (such as loperamide and diphenoxy thereof. late) and cholestyramine for diarrhea. However, Such therapy has proven to have limited, if any, efficacy. 0015 Methods of treating or preventing gastrointestinal disorders using the above compositions are also disclosed. 0006 Clearly, therefore, a significant unmet need remains for an efficacious and comprehensive treatment of DETAILED DESCRIPTION OF THE patients afflicted with Such lower GI disorders, including INVENTION alleviation of Such lower GI symptoms as chronic diarrhea, constipation and cramps. 0016 All percentages and ratios used herein are by weight of the total composition and all measurements made 0007. The present inventors have found that gastrointes are at 25.degree. C., unless otherwise designated. tinal compositions comprising a gamma-aminobutyric acid analogs in combination with Select gastrointestinal actives 0017. The compositions of the present invention can provide a more comprehensive reduction in IBS Symptoms comprise, consist essentially of, or consist of, the essential as compared to previous drug therapies. as well as optional ingredients and components described herein. AS used herein, "consisting essentially of means 0008 Accordingly, an aspect of the present invention is that the composition or component may include additional to provide gastrointestinal compositions. ingredients, but only if the additional ingredients do not 0009. Another aspect of the present invention is to pro materially alter the basic and novel characteristics of the vide gastrointestinal compositions which prevent, reduce or claimed compositions or methods. alleviate the symptoms associated with IBS. 0018 All publications cited herein are hereby incorpo 0010) A further aspect of the present invention is to rated by reference in their entirety. provide gastrointestinal compositions comprising amino 0019 AS used herein, a “pharmaceutically acceptable” ether and/or ester oxides in combination with gastrointesti component is one that is Suitable for use with humans and/or nal actives Selected from the group consisting of laxatives, animals without undue adverse side effects (Such as toxicity, antidiarrheals, antibiotics, antiulceratives, gastric Secretion irritation, and allergic response) commensurate with a rea inhibitors, peristalitic Stimulants, Serotonin (5HT) receptor Sonable benefit/risk ratio. US 2004/0013741 A1 Jan. 22, 2004

0020. By “safe and effective amount” is meant an amount nitro, a pyridyl radical or a lower alkyl radical, Q is -O- of a compound or composition which is high enough to or -COO-, n is equal to Zero, 1 or 2, m and q are, positively modify the condition being treated, but low independently of one another, equal to Zero or to 1, p is an enough to avoid Serious Side effects at a reasonable benefit/ integer ranging from 0 to 9. risk ratio within the Scope of Sound medical judgement. The Safe and effective amount may vary with the age and 0026. By lower radical are meant radicals having from 1 physical condition of the perSon being treated, the Severity to 10 carbon atoms, preferably 1 to 6 carbon atoms, espe of the condition, the Specific ingredients employed, and like cially 1 to 4 carbon atoms in a Straight or branched chain. factors. 0027) If R is alkyl, it is preferably methyl. If the amino 0021. The phrase “gastrointestinal disorder', as used ether oxides are halogenated, they are preferably brominated herein, means a disorder of the gastrointestinal tract, includ or chlorinated. ing the Small and large intestines and the rectum, and/or 0028. The invention also embraces the acid addition salts Symptoms usually attributed to a dysfunction of one or more of amino-ether oxides, notably those of mineral acids, Such of these organs, Such as diarrhea, constipation and/or as halohydrates, Sulphates, phosphates, or organic acids Such abdominal and lower abdominal cramping or pain. It is as maleates, citrates, malates, tartrates, methaneSulphonates, understood that gastro intestinal disorders include both camphoSulphonates, benzoates, etc. disorders for which an organic cause (e.g. infection by a parasite) is known and disorders for which no organic cause 0029. The invention further covers both racemic and can be ascertained, Such as IBS. Gastrointestinal disorders, optionally active forms which can be separated, particularly therefore, include, but are not limited to, irritable bowel by forming Salts with optically active acids. Syndrome, functional diarrhea, ulcerative colitis, collag 0030 Examples of suitable amino-ether and/or -ester enous colitis, microscopic colitis, lymphocytic colitis, oxides include trimebutine (3,4,5-trimethoxybenzoic acid inflammatory bowel disease, Crohn's disease, and infectious 2-(dimethylamino)-2-phenylbutyl ester), fedotozine ((R)-O- diarrhea Such as diarrhea associated with amebiasis, giar ethyl-N,N-dimethyl-O-I(3,4,5-trimethoxyphenyl) meth diasis, a viral infection, cytomegalovirus infection, or a oxymethylbenenemethanamine) and mixtures thereof. pathogenic bacterial infection. The bacterial infection may, for example, be an infection by a bacterium Selected from 0031 Trimebutine is available under the tradenames the group consisting of a bacterium of the genus Escherichia, Modulon (Canada), Debridat (Italy), Cerekinon (Japan), and an Escherichia coli O157:H7 bacterium, a bacterium of the Polibutin (Spain). A more detailed description of Fedotozine genus Salmonella, a bacterium of the genus Shigella, a can be found in U.S. Pat. No. 4,301,163 to Torossian et al. bacterium of the genus Campylobacter, a bacterium of the (1981) and U.S. Pat. No. 5,245,080 to Aubard et al. (1993), Species Campylobacter jejuni, and a bacterium of the genus both of which are herein incorporated by reference in their Yersinia entirety. 0022. The gastrointestinal compositions of the present 0032) Fedotozine has been administered effectively at invention, including the essential and optional components dosages of up to 210 mg daily, preferably 30 to 70 mg three thereof, are described in detail hereinafter. times daily, and up to 100 mg intravenously daily. Trime butine has been effectively administered orally at up to 600 ESSential Ingredients mg/day, preferably up to 200 milligrams 3 times daily, or intramuscularly/intravenously at up to 100 milligrams every 0023 Amino-Ether and/or Ester Oxides 12 hours. While mindful of individual patient parameters and Symptom Severity, the amino-ether and/or ester oxides 0024. The compositions and methods of the present are preferably administered orally at 1-75 mg/kg, preferably invention comprise a Safe and effective amount of an amino ether and/or -ester oxide. Amino-ether and/or -ester oxides 2-50 mg/kg and most preferably at 5-20 mg/kg. according to the invention conform to the formula: 0033 Gastrointestinal Actives 0034. The compositions also comprise a safe and effec tive amount of a gastrointestinal active. In one embodiement R4 the gastrointestinal active is Selected from the group con (CH2) Sisting of laxatives, antidiarrheals, antibiotics, antiulcer atives, gastric Secretion inhibitors, peristalitic Stimulants, (5HT) receptor antagonists, Serotonin (5HT) receptor ago (CH2) g nists, Selective Serotonin reuptake inhibitors and mixtures thereof. 0035) Suitable gastrointestinal actives include, but are not limited to, the following: 0.025 in which: R is a lower alkyl, R and R which are 0036 Laxatives the same or different are hydrogen or lower alkyl, R is a 0037. A safe and effective amount of a laxative may be phenyl or phenoxy nucleus optionally monoSubstituted to added to the compositions of the subject invention. The trisubstituted by Substituents which are identical or different, exact amount of laxative to be used in the compositions will halogen or lower alkoxy, R is a phenyl radical optionally depend on the particular laxative utilized since Such agents monosubstituted to trisubstituted by Substituents which are vary widely in potency. A more complete description of the the same or different, halogen, lower alkyl, lower alkoxy or various laxatives, including acceptable laxative effective US 2004/0013741 A1 Jan. 22, 2004 amounts thereof for use in unit dose compositions of the (dried), , , , , present invention can be found in U.S. Pat. No. 5,516,524; eSaprazole, , ftaxilide, , guaiaZulene, herein incorporated by reference in its entirety; as well as the irSogladine, , , ornoprostil, Y-ory Zanol, Handbook of Nonprescription Drugs, 12th Ed., Chapter 12, pifarnine, , plaunotol, , rioprostil, pp. 279-290 (American Pharmaceutical Association, Wash rosaprostol, rotraxate, , , Spizo ington, D.C.; 2000); and DrugFacts and Comparisons (54th furone, , , trimoprostil, thrithiozine, troX Ed. 2000), pp. 1166-1177; the cited pages of which are ipide, and . Mixtures of the above antiulcerative herein incorporated by reference. can also be used. 0.038 Laxatives useful herein include, but are not limited 0045 Antibiotics to, hydrophilic derivatives of cellulose (such methylcellu lose and carboxymethylcellulose Sodium), malt Soup extract, 0046 Asafe and effective amount of an antibiotic may be polyacrylic resins (preferably hydrophilic forms Such as added. The exact amount of antibiotic to be used in the polycarbophil and calcium polycarbophil), plantago Seeds, compositions will depend on the particular antibiotic utilized psyllium husk, dioctyl calcium SulfoSuccinate, dioctyl potas Since Such agents vary widely in potency. sium SulfoSuccinate, dioctyl Sodium SulfoSuccinate, mineral 0047 A wide variety of antibiotics may be used accord oil, magnesium citrate, magnesium hydroxide, magnesium ing to the invention, including for example nitroimidazole Sulfate, dibasic Sodium phosphate, monobasic Sodium phos antibiotics (e.g. tinidazole or metronidazole), tetracyclines phate, Sodium biphosphate, glycerin, anthraquinones or (e.g. tetracyclin, doxycyclin and minocyclin), pencillins anthracene laxatives (Such as aloe, cascara Sagrada, dan (e.g. amoxycillin, amplicillin and meZlocillin), cephalospor thron, Senna, aloin, casanthranol, frangula, and rhubarb), ins (e.g. cefachlor, cefadroxil, cephradine, cefuroxime, diphenylmethanes (Such as bisacodyl and phenolphthalein), cefuroxime axetil, cephalexin, cefpodoxime proxetil, and castor oil. Mixtures of the above laxatives can also be ceftazidime and ceftriaxone), carbopenems (e.g. imipenem used. and meropenem), amino-glycosides (e.g. paromonycin), macrollide antibiotics (e.g. erythromycin, clarithromycin and 0039) Antidiarrheals azithromycin), lincosamide antibiotics (e.g. clindamycin), 0040 Asafe and effective amount of an antidiarrheal may 4-quinolones (e.g. ofloxacin, ciprofloxacin, pefloxacin and be added to the compositions of the subject invention. The norfloxacin), rifamycins (e.g. rifampicin), nitrofurantoin and exact amount of the antidiarrheal to be used in the compo derivatives of 10-(1-hydroxyethyl)-11-oxo-1-azatricyclo Sitions will depend on the particular antidiarrheal utilized 7.2.0.0.3.8 undec-2-ene-2-carboxylic acid and mixtures Since Such agents vary widely in potency. A more complete thereofas well as those described in U.S. Pat. No. 5,719, 197 description of the various antidiarrheals, including accept to Kanios et al. (1998), published European Patent Specifi able antidiarrheal effective amounts thereof for use in unit cation No. 0416953 and published International Patent dose compositions of the present invention can be found in Specification No. WO92/03437, each of which are herein the Handbook of Nonprescription Drugs, 12th Ed., Chapter incorporated by reference in its entirety. 13, pp. 312-316 (American Pharmaceutical ASSociation, Washington, D.C.; 2000); and Drug Facts and Comparisons 0048 Mixtures of any of the above-mentioned antibiotic (54th Ed. 2000), pp. 1178-1182; the cited pages of which are compounds can also be used. herein incorporated by reference. 0049 Gastric Secretion Inhibitors 0041 Antidiarrheals useful herein include, but are not 0050 A safe and effective amount of a gastric secretion limited to, natural or Synthetic opiates (Such as difenoxin, inhibitor may be added to the compositions of the subject diphenoxylate, pargoric, opium tincture, and loperamide), invention. Suitable gastric Secretion inhibitors include, but anticholinergics (Such as belladonna alkoloids-atropine are not limited to, enterogastrone and Octreotide. The exact hyoscyamine, and hyosine), acetyltannic acid, albumin tan amount of gastric Secretion inhibitors to be used in the nate, alkofanone, aluminum Salicylates, catechin, lidami compositions will depend on the particular gastric Secretion dine, mebiquine, trillium, and uZarin. Mixtures of the above inhibitor utilized Since Such agents vary widely in potency. antidiarrheals can also be used. A more complete description of the various Gastric Secre 0042 Antiulcerative tion Inhibitors, including acceptable e Gastric Secretion Inhibitor effective amounts thereof for use in unit dose 0.043 A safe and effective amount of an antiulcerative compositions of the present invention can be found in the may be added to the compositions of the Subject invention. Drug Facts and Comparisons (54th Ed. 2000), pp. 352-354; The exact amount of the antiulcerative to be used in the the cited pages of which are herein incorporated by refer compositions will depend on the particular antiulcerative ence. Mixtures of the above gastric Secretion inhibitors can utilized Since Such agents vary widely in potency. A more also be used. complete description of the various antiulceratives, includ ing acceptable antiulcerative effective amounts thereof for 0051 Peristaltic Stimulants use in unit dose compositions of the present invention can be 0052 Asafe and effective amount of a peristaltic stimu found in the Drug Facts and Comparisons (54th Ed. 2000), lant may be added to the compositions of the Subject pp. 1131-1139; the cited pages of which are herein incor invention. Suitable peristaltic Stimulants include, but are not porated by reference. limited to, dexpanthenol, metoclopromide, cisapride, and 0044 Antiulcerative useful in the present invention domperidone. The exact amount of peristalitic Stimulants to include, but are not limited to, aluminum be used in the compositions will depend on the particular complex, e-acetamidocaproic acid Zinc Salt, , peristalitic Stimulant utilized since Such agents vary widely in arbaprostil, benexate hydrochloride, Sol potency. A more complete description of the various, Peri US 2004/0013741 A1 Jan. 22, 2004 staltic Stimulants including acceptable Peristaltic Stimulant the cited pages of which are herein incorporated by refer effective amounts thereof for use in unit dose compositions ence. Mixtures of the above Selective Serotonin reuptake of the present invention can be found in the Drug Facts and inhibitors can also be used. Comparisons (54th Ed. 2000), pp. 1188-1193; the cited pages of which are herein incorporated by reference. Mix 0059 Preferred for use herein as the gastrointestinal tures of the above peristalitic Stimulants can also be used. active are bulk forming laxatives Such as methylcellulose, carboxymethylcellulose Sodium, malt Soup extract, hydro 0053 Serotonin (5HT.) Receptor Antagonist philic polyacrylic resins, plantago Seeds, psyllium husk and 0054 Asafe and effective amount of a serotonin (5HT) mixtures thereof. Most preferred for use herein are hydro receptor antagonist may be added to the compositions of the philic polyacrylic resins Such as polycarbophil and/or cal subject invention. Suitable serotonin (5HT) receptor cium polycarbophil. Calcium polycarbophil is monographed antagonists include, but are not limited to, cilansetron, and every unit contains 500 mg of polycarbophil (650 mg dolasetron, Ondansetron, aloSetron and mixtures thereof. The polycarbophil) with a dosing of 2 units(1 gm polycarbophil) exact amount of Serotonin (5HT) receptor antagonists to be up to 4 times a day and, preferably not to exceed 12 units (6 used in the compositions will depend on the particular gm) in a 24 hour period. Serotonin (5HT) receptor antagonist utilized since Such agents vary widely in potency. A more complete description 0060) Further dosage information concerning disclosed of the various Serotonin (5HT) receptor antagonists, includ actives is Summarized in the table below: ing acceptable effective amounts thereof for use in unit dose compositions of the present invention can be found in U.S. Pat. No. 6,235,745, herein incorporated by reference and the Suitable Strengths and Drug Facts and Comparisons (54th Ed. 2000), pp. 869-872 Dosage Forms (Brand and KU47; the cited pages of which are herein incorporated Generic Name Names) Usual Adult Dosage by reference. Mixtures of the above serotonin (5HT) recep Bulk-Foaming tor antagonists can also be used. Laxatives 0055 Serotonin (5HT.) Receptor Agonist Calcium polycarbophil 625-mg tablets that 1-6 g/day as poly provide 500 mg of carbophil in divided 0056 Asafe and effective amount of a serotonin (5HT) polycarbophil doses receptor agonist may be added to the compositions of the (Konsyl Fiber) Methylcellulose 2 g/Tbsp oral powder 4-6 g/day in divided Subject invention. Suitable serotonin (5HT) receptor ago (Citrucel) doses nists include, but are not limited to tegaserod, renZapride and Psyllium 3.4 g/tsp or 3.4 g/Tbsp 2.5-30 g/day in prucalopride. The exact amount of Serotonin (5HT) recep oral powder; 1.7 g wafer divided doses tor agonists to be used in the compositions will depend on (Metamucil) Antidiarrheals (opiate the particular Serotonin (5HT) receptor agonist utilized and anticholinergic Since Such agents vary widely in potency. Tegaserod is a agents) partial Serotonin (5HT) receptor agonist which accelerates Orocecal transit (without effect on gastic emptying) and Diphenoxylate 2.5-mg tablets; 2.5 2.5-5 mg four times mg/5 mL oral liquid daily as needed for tends to enhance colonic transit. 12 mg/day of tegaserod is (Lomotil) diarrhea taught to result in effective relief of irritable bowel syndrome Loperamide 2-mg tablets and 2-4 mg up to four symptoms. Prucalopride is a full serotonin (5HT) receptor capsules; 1 mg/5 mL times daily as needed. agonist which accelerates gastric, Small bowel and colonic oral liquid (Imodium) Dicyclomine 10-mg capsules; 20-mg 10-20 mg three or transit in functional constipation. Up to 4 mg/day, particu tablets; 10 mg/5 mL four times daily larly 2-4 mg/day, of prucalopride is taught to result in syrup (Bentyl) effective relief of untoward bowel symptoms. Renzapride Hyoscyamine 0.125-mg tablets; 0.125 0.15-0.3 mg up to possesses both Serotonin (5HT) receptor agonist and Sero mg/mL, 0.125 mg/5 four times daily mL elixir (Levsin) tonin (5HT) receptor antagonist activity, providing Tincture of bellonna Tincture with 0.3 0.6-1 mL three or four increased gastric emptying and reduced gastrintestinal tran mg/mL alkaloids of times daily sit time. Mixtures of the above serotonin (5HT) receptor belladonna leaf agonists can also be used. Peristaltic Stimulants Cisapride 10-, 20-mg tablets; 5 5-10 mg three times 0057 Selective Serotonin Reuptake Inhibitors mg/mL oral suspension daily (Propulsid) 0.058 Asafe and effective amount of a selective serotonin Metoclopramide 5-, 10-mg tablets; 5 reuptake inhibitor may be added to the compositions of the mg/5 mL oral liquid Subject invention. Suitable Selective Serotonin reuptake Selective Serotonin inhibitors include, but are not limited to, fluoxetine, fluvox Reuptake Inhibitors amine, paroxetine, and Sertraline. The exact amount of Fluoxetine 20-mg capsules; 20 Selective Serotonin reuptake inhibitors to be used in the mg/5 mL oral solution compositions will depend on the particular Selective Sero (Prozac) tonin reuptake inhibitor utilized since Such agents vary Fluvoxamine 50-, 100-mg tablets widely in potency. A more complete description of the (Luvox) Paroxetine 10 mg/5 mL oral various Selective Serotonin reuptake inhibitors, including suspension; 10-, 20-, acceptable effective amounts thereof for use in unit dose 30-, 40-mg tablets compositions of the present invention can be found in the (Paxil) Drug Facts and Comparisons (54th Ed. 2000), pp. 918-928; US 2004/0013741 A1 Jan. 22, 2004

used. Mixtures of the above steroidal anti-inflammatory -continued agents can also be used. The preferred Steroidal anti-inflam matory for use is . Suitable Strengths and Dosage Forms (Brand 0063 A second class of anti-inflammatory agents which Generic Name Names) Usual Adult Dosage is useful in the compositions includes the nonsteroidal Sertraline 25-, 50-, 100-mg tablets anti-inflammatory agents. The variety of compounds encom (Zoloft) passed by this group are well-known to those skilled in the Serotonin (5HT) art. For detailed disclosure of the chemical Structure, Syn Receptor Antagonist thesis, Side effects, etc. of non-Steroidal anti-inflammatory Alosetron 1-mg tablets (Lotronex) 1 mg twice daily agents, reference may be had to Standard texts, including Granisetron 1-mg tablets (Kytril) Anti-inflammatory and Anti-Rheumatic Drugs, K. D. Rain Ondansetron 4-, 8-mg tablets 4 mg three times daily sford, Vol. I-III, CRC Press, Boca Raton, (1985), and (Zofran) Anti-inflammatory Agents, Chemistry and Pharmacology 1, Gastric Secretion Inhibitors R. A. Scherrer, et al., Academic Press, New York (1974), each incorporated herein by reference. Octreotide 50, 100, 200, 500, 1000 pig?mL sterile solution 0064. Specific non-steroidal anti-inflammatory agents for s.c. or i.v. injection useful in the composition invention include, but are not (Sandostatin); 10-, 20-, limited to: 30-mg sterile suspension for i.m. 0065. 1) the oxicams, such as piroxicam, isoxicam, injection (Sandostatin LAR Depot) tenoxicam, Sudoxicam, and CP-14304; CNS = central nervous system; GI = gastrointestinal; 5-HT3 = serotonin 0066 2) the salicylates, such as aspirin, disalcid, (5-hydroxytryptamine) receptor subtype 3; i.m. = intramuscular; i.v. = benorylate, trilisate, Safapryn, Solprin, diflunisal, and intravenous; s.c. = Subcutaneous. fendosal; 0067 3) the acetic acid derivatives, such as Optional Ingredients diclofenac, fenclofenac, indomethacin, Sulindac, tol 0061. A safe and effective amount of an anti-inflamma metin, isoxepac, furofenac, tiopinac, Zidometacin, tory agent may be added to the compositions of the Subject acematacin, fentiaZac, Zomepirac, clindanac, OXepi invention. The exact amount of anti-inflammatory agent to nac, felbinac, and ketorolac, be used in the compositions will depend on the particular 0068 4) the fenamates, such as mefenamic, anti-inflammatory agent utilized since Such agents vary meclofenamic, flufenamic, niflumic, and tolfenamic widely in potency. A more complete description of the acids, various NSAID's, including acceptable analgesically effec tive amounts thereof for use in unit dose compositions of the 0069 5) the propionic acid derivatives, such as present invention also appears in applicants co-pending U.S. ibuprofen, naproxen, benoxaprofen, flurbiprofen, application Ser. No. 474,358, filed Mar. 11, 1983, and now ketoprofen, fenoprofen, fenbufen, indopropfen, pir U.S. Pat. No. 4,486,436, and Ser. No. 578,288, filed Feb. 8, profen, carprofen, oxaprozin, pranoprofen, miropro 1984, now U.S. Pat. No. 4,522,826 the entire disclosures of fen, tioxaprofen, Suprofen, alminoprofen, and tiapro which are incorporated herein by reference. fenic, and 0.062 Steroidal anti-inflammatory agents, including but 0070) 6) the pyrazoles, such as phenylbutazone, not limited to, Such as hydrocortisone, OxyphenbutaZone, feprazone, azapropaZone, and tri hydroxyltriamcinolone, alpha-methyl , dex methaZone. amethasone-phosphate, beclomethasone dipropionates, clo betasol Valerate, , desoxymethasone, desoxycorti 0071 Mixtures of these non-steroidal anti-inflammatory costerone acetate, dexamethasone, , agents may also be employed, as well as the pharmologically diacetate, Valerate, fluadrenolone, fluclo acceptable Salts and esters of these agents. For example, rolone acetonide, , flumethasone pivalate, etofenamate, a flufenamic acid derivative, is particularly fluosinolone acetonide, , flucortine butylesters, useful for topical application. Of the nonsteroidal anti , (fluprednylidene) acetate, flu inflammatory agents, ibuprofen, naproxen, flufenamic acid, randrenolone, , hydrocortisone acetate, hydro etofenamate, aspirin, mefenamic acid, meclofenamic acid, butyrate, , piroXicam and felbinac are preferred; ibuprofen, naproxen, acetonide, cortisone, cortodoxone, flucetonide, fluidrocorti etofenamate, aspirin and flufenamic acid are most preferred. Sone, difluoroSone diacetate, fluradrenolone, fluidrocorti 0072 Finally, so-called “natural' anti-inflammatory Sone, difluroSone diacetate, fluradrenolone acetonide, agents are useful in methods of the Subject invention. Such , amcinafel, , and the agents may Suitably be obtained as an extract by Suitable balance of its esters, , chlorprednisone physical and/or chemical isolation from natural Sources acetate, clocortelone, cleScinolone, dichlorisone, diflurpred (e.g., plants, fungi, by-products of microorganisms). For nate, flucloronide, , fluoromethalone, , example, candelilla wax, alpha bisabolol, aloe Vera, Man , hydrocortisone Valerate, hydrocortisone jistha (extracted from plants in the genus Rubia, particularly cyclopentylpropionate, , , Rubia Cordifolia), and Guggal (extracted from plants in the , , , beclomethasone genus Commiphora, particularly Commiphora Mukul), kola dipropionate, triamcinolone, and mixtures thereof may be extract, chamomile, and Sea whip extract, may be used. US 2004/0013741 A1 Jan. 22, 2004

Additional anti-inflammatory agents useful herein include 0078. Of course, additionally, the compositions of the compounds of the Licorice (the plant genus/species Glycyr present invention may be formulated in Sustained release rhiza glabra) family, including glycyrrhetic acid, glycyr form to provide the rate controlled release of any one or rhizic acid, and derivatives thereof (e.g., Salts and esters). more of the components to optimize the therapeutic effects, Suitable Salts of the foregoing compounds include metal and i.e., analgesia, Skeletal muscle relaxation, etc. while mini ammonium salts. Suitable esters include C-C Saturated or mizing undesirable Side effects. Suitable dosage forms for unsaturated esters of the acids, preferably Co-C, more Sustained release include layered tablets containing layers of preferably C-C. Specific examples of the foregoing varying disintegration rates or controlled release polymeric include oil Soluble licorice extract, the glycyrrhizic and matrices impregnated with the active components and glycyrrhetic acids themselves, monoammonium glycyrrhiz shaped in tablet form or capsules containing Such impreg inate, monopotassium glycyrrhizinate, dipotassium glycyr nated or encapsulated porous polymeric matrices. rhizinate, 1-beta-glycyrrhetic acid, Stearyl glycyrrhetinate, and 3-Stearyloxy-glycyrrhetinic acid, and disodium 3-Succi 0079 Similarly, injectable dosage units may be utilized nyloxy-beta-glycyrrhetinate. Stearyl glycyrrhetinate is pre to accomplish intravenous, intramuscular or Subcutaneous administration and, for Such parenteral administration, Suit ferred. able Sterile aqueous or non-aqueous Solutions or Suspen 0.073 Mixtures of any of the above anti-inflammatory Sions, optionally containing appropriate Solutes to effectuate agents can also be used. isotonicity, will be employed. 0074 Carriers 0080 Specific examples of pharmaceutical acceptable 0075. In accordance with the practices of the present carriers and excipients that may be used to formulate oral invention, the gastrointestinal compositions may be admin dosage forms of the present invention are described in U.S. istered in admixture with Suitable pharmaceutical diluents, Pat. No. 3,903,297 to Robert, issued Sep. 2, 1975, herein carriers or other excipients (collectively referred to as "car incorporated by reference in its entirety. Techniques and rier” materials) suitably selected with respect to the intended compositions for making dosage forms useful in the present route of administration and conventional pharmaceutical invention are described in the following references: 7 Mod practices. The gastrointestinal compositions of the present ern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, invention are typically mixed with a pharmaceutically Editors, 1979); acceptable carrier. This carrier can be a Solid or liquid and 0081 Lieberman et al., Pharmaceutical Dosage Forms: the type is generally chosen based on the type of adminis Tablets (1981); and Ansel, Introduction to Pharmaceutical tration being used. Dosage Forms 2nd Edition (1976), each of which are herein 0.076 The actives can be coadministered in the form of a incorporated by reference in its entirety. tablet or capsule, liposome, as an agglomerated powder or in 0082 The gastrointestinal compositions of the present a liquid form. Capsule or tablets can be easily formulated invention may also be formulated and administered by other and can be made easy to Swallow or chew; other Solid forms methods known for administering gastrointestinal actives. include granules, and bulk powders. Tablets may contain For example, the composition may be adapted for topical Suitable binders, lubricants, diluents, disintegrating agents, administration in the form of rectal preparations Such as a coloring agents, flavoring agents, flow-inducing agents, and rectal cream, gel, ointment, or Suppository. melting agents. Examples of Suitable liquid dosage forms include Solutions or Suspensions in water, pharmaceutically 0.083 Method of Treatment acceptable fats and oils, alcohols or other organic Solvents, 0084. The method of treatment can be any suitable including esters, emulsions, Syrups or elixirs, Suspensions, method which is effective in the treatment of the particular Solutions and/or Suspensions reconstituted from non-effer type of lower gastrointestinal disorder that is being treated. Vescent granules and effervescent preparations reconstituted Treatment may be oral, rectal, parenteral, intravenous from effervescent granules. Such liquid dosage forms may administration or injection. The method of applying an contain, for example, Suitable Solvents, preservatives, emul effective amount also varies depending on the lower gas Sifying agents, Suspending agents, diluents, Sweeteners, trointestinal disorder being treated. It is believed that oral thickeners, and melting agents. Oral dosage forms optionally treatment by tablet, capsule or liquid will be the preferred contain flavorants and coloring agents. method of administering the compounds to warm blooded 0.077 Examples of suitable tablet or capsule form ingre mammals. dients, include but are not limited, to oral non-toxic phar 0085. The method of treating lower gastrointestinal dis maceutically acceptable inert carrier Such as lactose, Starch, orders may also be by rectal, parenteral, or intravenous Sucrose, cellulose, magnesium Stearate, dicalcium phos administration. The actual time and dosage will depend on phate, calcium Sulfate, mannitol and the like. Moreover, the type of the lower gastrointestinal disorder being treated when desired or necessary, Suitable binders, lubricants, and the desired blood levels. disintegrating agents and coloring agents can also be incor porated in the mixture. Suitable binders include Starch, EXAMPLES gelatin, natural Sugars, corn Sweeteners, natural and Syn thetic gums Such as acacia, Sodium alginate, carboxymeth 0086 The compositions in the following illustrate spe ylcellulose, polyethylene glycol and waxes. Among the cific embodiments of the gastrointestinal compositions of lubricants there may be mentioned for use in these dosage the present invention, but are not intended to be limiting forms, boric acid, Sodiumbenzoate, Sodium acetate, Sodium thereof. Other modifications can be undertaken by the chloride, etc. Disintegrators include, without limitation, skilled artisan without departing from the Spirit and Scope of Starch, methylcellulose, agar, bentonite, guar gum, etc. this invention. US 2004/0013741 A1 Jan. 22, 2004

0.087 All exemplified compositions can be prepared by Example III conventional formulation and mixing techniques. Compo 0092. The following is an example of an antiulcerative nent amounts are listed as weight percents and exclude tablet composition of the present invention. minor materials. Such as diluents, filler, and So forth. The listed formulations, therefore, comprise the listed compo nents and any minor materials associated with Such com ponents. Ingredient %fwfw Trimebutine 40.OOO Ranitidine HCL 3O.OOO Example I Microcrystalline 24.40 Cellulose 0088. The following is an example of an antidiarrheal Lactose 4.OOO capsule composition of the present invention. The capsule is Monohydrate formed by combining and mixing the ingredients of each Magnesium 1.60 column using conventional technology and transferring the Stearate NF mixture to an appropriate sized hard gelatin capsule for oral "Available as Avicel 102 supplied by FMC Corporation administration. *Supplied by Archer Daniel Midland Co. Magnesium Stearate (Light) supplied by Witco Corporation. 0093. In a suitable vessel, the trimebutine, ranitidine Ingredient %fwfw HCL, microcrystalline cellulose and lactuose monohydrate are milled to a Suitable size and mixed until homogeneous. Loperamide O.SOO The magnesium Strearate is added and the mixture is mixed Trimebutine SO.OOO until homogeneous. The mixture is then discharged and Corn Starch 27.OOO compressed using conventional tablet tooling to a Suitable USP1 hardness (e.g., 10-12 kp) to target a net table weight of 500 Talc USP 7.5 mg. The tablet is administered orally. Lactose 15.OOO Monohydrate What is claimed is: 1. A composition for treating or preventing gastrointesti nal disorders, comprising: "Corn Starch Modified supplied by National Starch and Chemical Co. a.) a safe and effective amount of an amino-ether and/or *Supplied by Whittaker, Clark & Daniels, Inc. -ester oxide having the formula: Supplied by Archer Daniel Midland Co. 0089. Once mixed the ingredients are incoporated into #2 R4 hard gelatin capsules composed of gelatin, titanium dioxide (CH2) and colorant and administered orally.

Example II (CH2) g 0090 The following is an example of a Trimebutine laxative combination capsule composition of the present invention. The capsule is formed by combining and mixing the ingredients of each column using conventional technol in which: R is a lower alkyl, R and R which are the ogy and transferring the mixture to an appropriate sized hard Same or different are hydrogen or lower alkyl, R is gelatin capsule for oral administration. a phenyl or phenoxy nucleus optionally monoSub stituted to trisubstituted by Substituents which are identical or different, halogen or lower alkoxy, Rs is a phenyl radical optionally monoSubstituted to Ingredient %fwfw trisubstituted by substituents which are the same or Trimebutine 25.OOO different, halogen, lower alkyl, lower alkoxy or nitro, Calcium SO.OOO a pyridyl radical or a lower alkyl radical, Q is -O- Polycarbophil or -COO-, n is equal to Zero, 1 or 2, m and q are, Microcrystalline 7.5 Cellulose NF independently of one another, equal to Zero or to 1, Talc USP 6.25.OOO p is an integer ranging from 0 to 9; and "Available as Avicel 102 supplied by FMC Corporation b.) a safe and effective amount of a gastrointestinal active *Supplied by Whittaker, Clark & Daniels, Inc. Selected from the group consisting of laxatives, antidi arrheals, antibiotics, antiulceratives, gastric Secretion inhibitors, peristalitic Stimulants, Serotonin (5HT) 0091. Once mixed the ingredients are incoporated into #2 receptor antagonists, Serotonin (5HT) receptor ago hard gelatin capsules composed of gelatin, titanium dioxide nists, Selective Serotonin reuptake inhibitor and mix and colorant and administered orally. tures thereof. US 2004/0013741 A1 Jan. 22, 2004

2. A composition according to claim 1, wherein the 10. A composition according to claim 1, wherein antibi laxative is Selected from the group consisting of methylcel otic is Selected from the group consisting of nitroimidazole lulose, carboxymethylcellulose Sodium, malt Soup extract, antibiotics, tetracyclines, pencillins, cephalosporins, car polyacrylic resin, plantago Seeds, dioctyl calcium SulfoSuc bopenems, amino-glycosides, macrollide antibiotics, lincosa cinate, dioctyl potassium SulfoSuccinate, dioctyl Sodium mide antibiotics, 4-quinolones, rifamycins, nitrofurantoin SulfoSuccinate, mineral oil, magnesium citrate, magnesium and derivatives of 10-(1-hydroxyethyl)-11-oxo-1-azatricy hydroxide, magnesium Sulfate, dibasic Sodium phosphate, clo7.2.0.0.3.8 undec-2-ene-2-carboxylic acid and mixtures monobasic Sodium phosphate, Sodium biphosphate, glyc thereof. erin, anthraquinones, diphenylmethanes, castor oil and mix 11. A composition according to claim 1, further compris tures thereof. ing an antiinflammatory compound. 12. A composition according to claim 11, wherein the 3. A composition according to claim 1, wherein the antiinflammatory compound is Selected from the group antidiarrheal is Selected from the group consisting of natural consisting of corticosteroids, non-Steroidal antiinflammatory opiates, Synthetic opiates, anticholinergics, acetyltannic compounds and mixtures thereof. acid, albumin tannate, alkofanone, aluminum Salicylates, 13. A composition according to claim 12, wherein the catechin, lidamidine, mebiquine, trillium, uZarin and mix antiinflammatory compound is a non-Steroidal antiinflam tures thereof. matory compound. 4. A composition according to claim 1, wherein the 14. A composition according to claim 1, in the form of a antiulcerative is Selected from the group consisting of ace tablet, capsule, microcapsule, Suspension, Solution, inject glutamide aluminum complex, e-acetamidocaproic acid Zinc able, rectal Suppository, rectal cream, rectal ointment, rectal Salt, acetoxolone, arbaprostil, benexate hydrochloride, bis gel. muth Subcitrate Sol (dried), carbenoxolone, cetraxate, cime 15. A composition according to claim 1, wherein the tidine, enproStil, esaprazole, famotidine, ftaxilide, gefarnate, amino-ether and/or -ester oxide Selected from the group guaiaZulene, irSogladine, nizatidine, omeprazole, ornopros consisting of trimebutine, fedotoZine and mixtures thereof. til, Y-ory Zanol, pifarnine, pirenzepine, plaunotol, ranitidine, 16. A composition according to claim 1, wherein the rioprostil, rosaprostol, rotraxate, roXatidine acetate, Sofal gastrointestinal active is a laxative. cone, Spizofurone, Sucralfate, teprenone, trimoprostil, 17. A composition according to claim 1, wherein the is thrithiozine, , Zolimidine and mixtures thereof. bulk forming laxative. 18. A composition according to claim 1, wherein the 5. A composition according to claim 1, wherein the gastric laxative is selected from the group consisting of polycarbo Secretion inhibitor is selected from the group consisting of phil, calcium polycarbophil and mixtures thereof. enterogastrone, octreotide and mixtures thereof. 19. A composition for treating or preventing gastrointes 6. A composition according to claim 1, wherein the tinal disorders, comprising: peristalitic Stimulant is Selected from the group consisting of metoclopromide, cisapride, domperidone and mixtures a.) a safe and effective amount of trimebutine, and thereof. b.) a safe and effective amount of polycarbophil. 7. A composition according to claim 1, wherein the 20. A composition for treating or preventing gastrointes Serotonin (5HT) receptor antagonist is selected from the tinal disorders, comprising: group consisting of renZapride cilansetron, Ondansetron, alosetron and mixtures thereof. a.) a safe and effective amount of fedotozine; and 8. A composition according to claim 1, wherein the c.) a safe and effective amount of polycarbophil. Serotonin (5HT) receptor agonist is selected from the group 21. A method of treating or preventing gastrointestinal consisting of tegaserod, prucalopride and mixtures thereof. disorders, comprising the Step of administering to a mammal 9. A composition according to claim 1, wherein the in need of Such treatment a Safe and effective amount of the Selective Serotonin reuptake inhibitor is Selected from the composition of claim 1. group consising of fluoxetine, fluvoxamine, paroxetine, Ser traline and mixtures thereof.