MXPA05000405A - Gastrointestinal compositions comprising gaba derivatives. - Google Patents

Abstract

The invention relates to compositions and methods for treating and/or preventing lower gastrointestinal (GI) disorders in mammalian patients, more particularly for alleviating and/or preventing the lower GI symptoms associated with such disorders.

Description

GASTROINTESTINAL COMPOSITIONS This continuation request partially claims priority to the utility application filed on July 10, 2002 by Express Mail N °. EL819323526US.

FIELD OF THE INVENTION The invention relates to compositions and methods for treating and / or preventing disorders of the lower gastrointestinal tract (Gl) in mammalian patients, more particularly to alleviate and / or prevent the symptoms of the lower Gl associated with such disorders.

BACKGROUND PE THE INVENTION The main function of the gastrointestinal tract is the absorption of the ingested nutrients. This is achieved when the transit along the esophagus and the gastrointestinal tract is at a speed which facilitates optimal digestion and absorption of water and electrolytes. Abnormal patterns in gastrointestinal motility result in a number of disorders ranging from diffuse esophageal spasm (an esophageal obstructive disorder characterized by dysphagia), achalasia (an obstructive disorder in which the lower esophageal sphincter fails to relax adequately resulting in dysphagia) and non-cardiac chest pain to functional bowel disorders such as irritable bowel syndrome (IBS), non-ulcer dyspepsia, and idiopathic constipation. IBS is particularly troublesome since it involves chronic episodes of diarrhea and / or constipation for which no organic cause has been identified. The disorder appears to result from defective regulation in both the nervous and gastrointestinal systems. Where drug therapy is indicated, therapy includes prokinetic agents for constipation, anticholinergics, antispasmodics such as trimebutine, serotonin reuptake inhibitor and tricyclic antidepressants, and sedatives for stomach cramps pain; and opiates (such as loperamide and definoxylate) and cholestyramine for diarrhea. However, such therapy has been shown to have limited efficacy, in the case of having any. Clearly, therefore, a significant unknown need remains for an effective and comprehensive treatment of patients afflicted with such disorders of the lower Gl, including relief of such symptoms of the lower Gl such as chronic diarrhea, constipation and cramps. The present invention has found that compositions consisting of gamma-aminobutyric acid analogues in combination with amino-ether oxides and / or ester oxides provide a more comprehensive reduction of IBS symptoms compared to previous drug therapies.

Accordingly, one aspect of the present invention is to provide gastrointestinal compositions. Another aspect of the present invention is to provide gastrointestinal compositions which prevent, reduce or alleviate the symptoms associated with IBS. A further aspect of the present invention is to provide gastrointestinal compositions consisting of gamma-aminobutyric acid analogs in combination with ammonium ester and / or ester oxides.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compositions for treating or preventing gastrointestinal disorders, consisting of: a) a GABA analogue of the formula selected from the group consisting of: H2N-CHJ -C- CHJCOZR, (CH2) N R3 R2 I I H2NCHCCH2COOH and mixtures thereof; and b) an amino ether oxide and / or an ester oxide having the formula: (CH2) "Rl- C- (CH2) m ^ Q- (CH2>, - R5 N / \ R2 R3 wherein: R1 is a lower alkyl, R2 and R3 which are the same or different are hydrogen or lower alkyl, R4 is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted by substituents which are identical or different, halogen or alkoxy lower, R5 is an optionally substituted phenyl radical of monosubstituted to trisubstituted by substituents which are identical or different, halogens, lower alkyl, lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical, Q is -O- or -COO- , n is equal to zero, 1 or 2, m and q are independently of each other, equal to zero or 1, p is an integer ranging from 0 to 9. Methods of treating or preventing gastrointestinal disorders using the compositions are also disclosed. previous DETAILED DESCRIPTION OF THE INVENTION All percentages and ratios used in this document are relative to the weight of the total compositions and all measurements made are at 2.5 degrees C, unless otherwise indicated. The compositions of the present invention may comprise, consist essentially of, or consist of, the essentials as well as optional ingredients and components described herein. As used herein, "consists essentially of" means that the composition or component may include additional ingredients, but only if the additional ingredients do not materially alter the new and basic characteristics of the claimed compositions and methods. All publications cited in the present document are hereby incorporated by reference in their entirety. As used in this document, a component "Pharmaceutically acceptable" is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation and allergic response) proportional to a reasonable benefit / risk ratio. By "safe and effective amount" is meant an amount of a compound or composition which is high enough to positively modify the condition being treated, but low enough to avoid serious side effects such as a reasonable benefit / risk ratio within the scope of the invention. solid medical judgment. The safe and effective amount may with the age and physical condition of the person being treated, the severity of the condition, the specific ingredients used, and similar factors. The phrase "gastrointestinal disorder," as used herein, means a disorder of the gastrointestinal tract, including the small and large intestine and rectum, and / or symptoms usually attributed to dysfunction of one or more of these organs, such as diarrhea, constipation and / or abdominal pain and cramps and abdominal pain. It is understood that gastrointestinal disorders include both disorders for which an organic cause is known (for example, infection by a parasite) and disorders for which no organic cause can be established, such as IBS. Gastrointestinal disorders, therefore, include, but are not limited to, irritable bowel syndrome, functional diarrhea, ulcerative colitis, collagenous colitis, microscopic colitis, lymphocytic colitis, inflammatory bowel disease, Crohn's disease, and infectious diarrhea such as diarrhea associated with amebiasis, giardiasis, a viral infection, infection with cytomegalovirus, or a pathogenic bacterial infection. The bacterial infection may, for example, be an infection by a bacterium selected from the group consisting of a bacterium of the genus Escherichia, an Escherichia co // 0157: H7 bacterium, a bacterium of the genus Salmonella, a bacterium of the genus Shigella, a bacterium bacteria of the genus Campylobacter, a bacterium of the species Campylobacter jejuni, and a bacterium of the genus Yersinia. The gastrointestinal compositions of the present infection, including the essential and optional components, are described in detail in a subsequent part of this document.

Qamma-aminobutyric acid analogues The compositions and methods of this infection utilize a safe and effective amount of gamma-aminobutyric acid analogues (GABA). A GABA analogue is a compound derived from or based on gamma-aminobutyric acid. The compounds are readily available, either commercially, or by synthesis methodology well known to those skilled in the art of organic chemistry. The GABA analogs used in the present invention are cyclic amino acids of Formula I. wherein R-i is hydrogen or lower alkyl and n is an integer from 4 to 6, and the pharmaceutically acceptable salts thereof. An especially useful embodiment uses a compound of Formula I wherein Ri is hydrogen and n is 5, which compound is 1- (aminomethyl) -cyclohexaneacetic acid, generally known as gabapentin. Also useful herein are GABA analogs of Formula I in which the cyclic ring is substituted, for example with alkyl groups such as methyl or ethyl. Typical compounds include (1-aminomethyl-3-methylcyclohexyl) acetic acid, (1-aminomethyl-3-methylcyclopentyl) acetic acid, and (1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid. Compounds and embodiments of Formula I are described in more detail in the U.S. Patent. 4,024,175; incorporated in this document by reference in its entirety. GABA analogs of Formula II are also useful in the present invention. R3 R2 I I H2NCHCCH2COOH N R. or a pharmaceutically acceptable salt thereof, wherein Ri is a linear or branched alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R2 is hydrogen or methyl; and R3 is hydrogen, methyl or carbonyl. Diastereomers or enantiomers of compounds of Formula II can be used in the invention where R2 and 3 are both hydrogen, and Ri is - (CH2) or-2-iC4H9 as an (R), (S), or (R, S) isomer ). Also useful herein are 3- (1-aminoethyl) -5-methylhexanoic acid, 3-aminomethyl-5-methyl-hexanoic acid, and (S) -3- (aminomethyl) -5-methylhexanoic acid (now known generically as pregabalin, as CI-1008). The compounds and embodiments represented by Formula II can be found in U.S. Patent 5,563,175, which is incorporated herein by reference in its entirety. The percentage of the active ingredient in the preceding compositions can be varied within wide limits, but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredient is present, for example, 10% to 90% by weight. The amount of GABA analogue in the composition will generally be from about 1 to about 300 mg per kg, preferably from about 5 to about 200 mg per kg, more preferably from about 10 to about 100 mg per kg of body weight of the subject. Typical doses will be from about 10 to about 5,000 mg, preferably from about 20 to about 800 mg, per day for an adult subject of normal weight. It is expected that common doses that can be administered can be 100 mg three times a day up to 600 mg four times a day. The useful intravenous dose is between 5 and 50 mg. (The intravenous dose is between the range of doses used in treatment of gastrointestinal diseases such as ulcers and IBS, or as would be imposed by the patient's needs as described by the physician). A more complete description of effective amounts of the same GABA analog acceptable for use in dose unit compositions of the present invention can be found in U.S. Patent Nos. 6,127,418 and 6,117,908, both of which are incorporated herein by reference in US Pat. its entirety Amino ether ether oxides and / or ester oxides The compositions and methods of the present invention may comprise a safe and effective amount of amino ether oxide and / or ester oxide. The amino ether oxides and / or the ester oxides according to the invention conform to the formula: wherein: Ri is a lower alkyl, R2 and R3 which are the same or different, are hydrogen or lower alkyl, R4 is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted by substituents which are identical or different, halogen or lower alkyl, R5 is a phenyl radical optionally monosubstituted to trisubstituted by substituents which are identical or different, halogen, lower alkyl, lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical, Q is -O- or -COO- , n is equal to zero, 1 or 2, m and q are, independently of each other, equal to zero or 1, p is an integer that ranges from 0 to 9. By active radical is meant radicals of 1 to 10 carbon atoms. carbon, preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms in a straight or branched chain. If R5 is alkyl, it is preferably methyl. If the amino ether oxides are halogenated, they are preferably brominated or chlorinated. The invention also includes the acid addition salts of amino ether oxides, notably those of mineral acids, such as halohydrates, sulfates, phosphates, or organic acids such as maleates, citrates, malate, tartrates, methanesulfonates, camphorsulfonates, benzoates, etc. . The invention further encompasses both racemic and optionally active forms which can be separated, particularly by forming salts with optically active acids. Examples of suitable amino ether oxides and / or ester oxides include trimebutine (2- (dimethylamino) -2-phenylbutyl ester of 3,4,5-trimethoxybenzoic acid), fedotozine ((R) -a-ethyl-N, N-dimethyl-a - [[(3,4,5-trimethoxyphenyl) methoxy] methyl] benzenemethanamine) and mixtures thereof. Trimebutine is available under the trade names Modulon (Canada), Debridat (lltalia), Cerekinon (Japan), and Polybutin (Spain). A more detailed description of fedotozin can be found in U.S. Patent 4,301, 163 assigned to Torosian et al. (1981) and U.S. Patent 5,245,080 assigned to Aubard et al. (1993), both of which are incorporated herein by reference in their entirety. The fedotozin has been effectively administered at dosages of up to 210 mg daily, preferably up to 200 milligrams 3 times daily, or intramuscularly / intravenously up to 100 milligrams every 12 hours. In spite of the conscious parameters of the individual patient and the severity of the symptoms, the amino ether oxides and / or the ether oxides are preferably administered orally at 1-75 mg / kg, preferably 2-50 mg / kg and the more preferable to 5-20 mg / kg. The compositions of the present invention may additionally contain: A. Anti-inflammatory agents A safe and effective amount of an anti-inflammatory agent must be added to the subject composition of the subject invention. The exact amount of anti-inflammatory agent to be used in the compositions will depend on the particular anti-inflammatory agent used since such agents vary widely in potency. A more complete description of several NSAIDs, including analgesically effective acceptable amounts thereof for use in the dose units of compositions of the present invention appears also in the applications of the United States, in process with the present document, of the applicants. Ser. NoS. 474,358, filed March 1, 1983, and now United States Patent No. 4,486.36; and 578,288, filed February 8, 1984, now U.S. Patent No. 4,522,826 the full disclosures of which are incorporated herein by reference. Steroidal antiinflammatory agents, including but not limited to, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alphamethyldexametasone, dexamethasone phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, deoxymethasone, deoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, valerate diflucortolone, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, acetonide fluosinolone, fluocinonide, butylesters of flucortine, fluocortolone, fluprednidene (fluprednylidene), flurandrenolone, halcionida, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone , shortdoxone, flucetonide, fludrocortisone, fluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone diacetate, fluradrenolone acetonide, medrisone, amcinafel, amcinafide, betamethasone and the rest of its esters, chloroprednisone, chloroplacetate rednisone, clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide, fluorometalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, parametasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures thereof can use. Mixtures of the above anti-inflammatory steroidal agents can also be used. The preferred steroidal anti-inflammatory for use is hydrocortisone. A second class of anti-inflammatory agents which are useful in composition include the non-steroidal anti-inflammatory agents. The variety of compounds comprised by this group are well known to those skilled in the art. For a detailed disclosure of the chemical structure, synthesis, side effects, etc., of non-steroidal anti-inflammatory agents, reference may be had to standard texts, including Anti-inflammatory and Anti-Rheumatic Drugs, K. D. Rainsford, vol. l.lll, CRC Press, Boca Raton, (1985), and Anti-inflammatory Agents, Chemistry and Pharmacology 1, R.A. Scherrer, et al., Academic Press, New York (1974), each incorporated herein by reference. Specific nonsteroidal antiinflammatory agents useful in the invention of the composition include, but are not limited to: 1) oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; 2) salicylates, such as aspirin, disalcid, benorilate, trilisate, safaprin, solprin, diflunisal, and fendosal; 3) acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, flurofenac, thiopinac, zidometacin, acematacin, fentiazac, zomepirac, clinandac, oxepinac, falbinac and ketorolac; 4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; 5) propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbutene, indoprophen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, thioxaprofen, suprofen, alminoprofen, and thiaprofenic; and 6) pyrazoles, such as phenylbutazone, oxyphenbutanone, pheorazone, azapropazone, and trimetazone.

Mixtures of the nonsteroidal anti-inflammatory agents can also be used, as can the pharmaceutically acceptable salts and esters of these agents. For example, etofenamate, a flufenamic acid derivative, is particularly useful for topical application. Of the non-steroidal anti-inflammatory agents, ibuprofen, naproxen, flufenamic acid, etofenamate, aspirin, mefenamic acid, meclofenamic acid, piroxicam and felbinac are preferred; most preferred are ibuprofen, naproxen, etofenamate, aspirin and flufenamic acid. Finally, the so-called "natural" anti-inflammatory agents are useful in processes of the subject invention. Such agents can be suitably obtained as an extract by physical and / or chemical isolation from natural sources (e.g., plants, fungi, microproduct by-products). For example, candelilla wax, alpha bisabolol, aloe vera, Manjistha (extracted from plants of the genus Commiphora, particularly Commiphora mukul), kola extract, chamomile, and Gorgon extract can be used. Additional antiinflammatory agents useful herein include compounds from the licorice family (the plant whose genus and species is Glycyrrhiza glabra), including glycyrrhizic acid, glycyrrhizic acid, and derivatives thereof (e.g., salts and esters). Suitable salts of the preceding compounds include metal and ammonium salts. Suitable esters include saturated or unsaturated C2-C24 esters of the acids, preferably C-io-C24, more preferably C16-C24. Specific examples of the foregoing include oil-soluble licorice extract, glycyrrhizic and glycyrrheic acid in themselves, monoammonium glycyrrhizinate, monopotassium glycyrrhizinate, dipotassium glycyrrhizinate, 1-beta-glycyrrhetic acid, stearyl glycyrrheinate, and 3-stearyloxyglycyrrhetinic acid, and 3-succinyloxy-beta-glycyrrheate. Stearyl glycyrrheinate is preferred. Mixtures of any of the above anti-inflammatory agents can also be used.

B. Laxatives A safe and effective amount of a laxative can be added to the compositions of the subject invention. The exact amount of laxative to be used in the compositions will depend on the laxative used in particular since such agents vary widely in potency. A more complete description of the various laxatives, including effective amounts of the same laxatives acceptable for use in unit dose compositions of the present invention, can be found in U.S. Patent 5,516,524; incorporated herein by reference in its entirety, as is the document Handbook of Nosprescription Drugs, 12th edition, chapter 12, pages 279-290 (American Pharmaceutical Association, Washington, D.C .; 2,000); and the Drug Facts and Comparisons document (54th edition, 2,000), pages 1, 166-1, 177; the cited pages of which are incorporated herein by reference. The laxatives useful in e! present document include, but are not limited to, hydrophilic cellulose derivatives (such as methylcellulose and sodium carboxymethylcellulose), malt soup extract, polyacrylic resins (preferably hydrophilic forms such as polycarbophil and calcium polycarbophil), plantain seeds, shells , dioctyl calcium sulfosuccinate, dioctyl sodium sulfosuccinate, mineral oil, magnesium citrate, magnesium hydroxide, magnesium sulfate, dibasic sodium phosphate, monobasic sodium phosphate, sodium biphosphate, glycerin, anthraquinone or anthraquinone laxatives (such as aloe, cascara sagrada, dantrona, senna, aloin, casantranol, frangula, and rhubarb), diphenylmethane (such as bisacodyl and phenolphthalein), and castor oil. Mixtures of the above laxatives can also be used.

C. Antidiarrheals A safe and effective amount of antidiarrheal can be added to the compositions of the subject invention. The exact amount of the antidiarrheal to be used in the compositions will depend on the particular antidiarrheal used since such agents can vary widely in potency. A more complete description of various antidiarrheals, including acceptable amounts of the same effective antidiarrheic for use in unit dose compositions of the present invention can be found in Handbook of Noscription, Drugs, 12th edition, chapter 12, pages 312-316 (American Pharmaceutical Association, Washington, D.C.; 2,000); and in the document Drug Facts and Comparisons (54th edition, 2,000), pages 1, 178-1,182; the aforementioned pages of which are incorporated herein by reference. Antidiarrheals useful herein include, but are not limited to, natural and synthetic opiates (such as diphenoxine, diphenoxylate, paregoric, opium tincture, and loperamide), anticholinergics (such as belladonna alkaloids -atropine, hicoscamine, and hyosine) , acetanilic acid, albumin tannate, alcofanone, aluminum salicylates, catechin, lidamidine, mebiquine, trillium and urazine. Mixtures of the above antidiarrheals can also be used.

D. Altiulcerativos A safe and effective amount of an antiulcerative can be added to the compositions of the subject invention. The exact amount of the antiulcerative to be used in the compositions will depend on the particular antiulcerative used since such agents can vary widely in potency. A more complete description of various antiulceratives, including acceptable amounts of the same effective antiulceratives for use in unit dose compositions of the present invention can be found in the document Drug Facts and Comparisons (54th edition, 2,000), pages 1, 131- 1, 139; the aforementioned pages of which are incorporated herein by reference. Antiulcerative agents useful in the present invention include, but are not limited to, aluminum acetoglutamide complex, zinc salt of e-acetamidocaproic acid, acetoxolone, arbaprostyl, benexate hydrochloride, bismuth subcitrate (dried), carbenoxolone, cetraxate, cimetidine , emprostilo, esaprazol, famotidina, phtaxilida, gefarnato, guaiazuleno, irsogladina, nizatidina, omeprazol, omoprostilo,? -orinazol, pifarnina, piranzepina, plaunotol, ranitidina, rioprostilo, rosaprostol, rotraxato, roxatidina acetate, sofalcona, spizofurona, sucralfato, teneprona , trimoprostilo, tritiozina, troxipida, and zolimidina. Mixtures of the above anti-ulcers can also be used.

E. Antibiotics A safe and effective amount of an antibiotic can be added to the compositions of the subject invention. The exact amount of antibiotic to be used in the composition will depend on the antibiotic used in particular since such agents can vary widely in potency. A complete description of the various antibiotics, including effective amounts of the same antibiotics acceptable for use in unit dose compositions can be found in the Drug Facts and Comparisons (54th edition, 2,000), pages 1, 2171-1, 354; the aforementioned pages of which are incorporated herein by reference. A wide variety of antibiotics can be used according to the invention, including for example nitroimidazole antibiotics (for example, tinidazole or metronidazole), tetracyclines (for example tetracycline, dosicillin and minocycline), penicillins (for example, amoxicillin, ampicillin, and mezlocillin), cephalosporins (eg, cefaclor, cefadroxil, cefaradine, cafuroxime, cefuroxma axetil, cephalexin, cefpodoxin proxetil, ceftazidime and ceftrlaxone), carbopenems (eg, mipenem and meropenem), aminoglycosides (eg, paromonicin), macrolide antibiotics (for example erythromycin, clarithromycin and azithromycin), antibiotics lincosamide (for example clindamycin), 4-quinolones (for example ofloxacin, ciprofloxacin, pefloxacin and norfloxacin); rifamycins (eg rifampicin), nitrofurantoin and 10- (1-hydroxyethyl) -11-oxo-1-azatricyclo [7.2.0.0.3.8] undec-2-ene-2-carboxylic acid derivatives and mixtures thereof than those described in U.S. Patent 5,719,197 to Kanios et al. (1998), published European patent application N °. 0416953 and published international patent application N °. WO92 / 03437, each of which is incorporated herein by reference in its entirety.

F. Gastric Secretion Inhibitors A safe and effective amount of a gastric secretion inhibitor can be added to subject compositions of the invention. Suitable inhibitors of gastric secretion include, but are not limited to, enterogastrone and octreotide. The exact amount of gastric secretion inhibitors to be used in the compositions will depend on the gastric secretion inhibitor used since such agents vary widely in potency. A more complete description of the various gastric secretion inhibitors, including effective amounts of the same gastric secretion inhibitor for use in unit dose compositions of the present invention can be found in the Drug Facts and Comparisons (54th edition, 2,000), pages 352-354; the aforementioned pages of which are incorporated herein by reference. Mixtures of the above gastric secretion inhibitors can also be used.

G. Peristaltic Stimulators A safe and effective amount of a peristaltic stimulator can be added to the compositions of the subject invention. Suitable peristaltic stimulators include, but are not limited to, dexpanthenol, metoclopromide, cisapride, and domperidone. The exact amount of peristaltic stimulators to be used in the compositions will depend on the particular peristaltic stimulator used since such agents vary widely in potency. A more complete description of the various peristaltic stimulators including effective amounts thereof for use in unit dose compositions of the present invention can be found in the document Drug Facts and Comparisons (54th edition, 2,000), pages 1, 188-1. , 193; the aforementioned pages of which are incorporated herein by reference. Mixtures of peristaltic stimulators can also be used.

H. Serotonin Receptor Antagonist (5HTj) A safe and effective amount of a serotonin receptor antagonist (5HT3) can be added to the compositions of the subject invention. Suitable serotonin receptor (5HT3) antagonists include, but are not limited to, cilasetrol, dolasetrol, ondasetron and alosetron. The exact amount of serotonin receptor antagonists (5HT3) to be used in the compositions will depend on the particular serotonin receptor (5HT3) antagonist used since such agents vary widely in potency. A more complete description of the various serotonin receptor antagonists (5HT3), including effective amounts thereof for use in unit dose compositions of the present invention can be found in US Pat. No. 6,235,745, incorporated herein by reference. present document by reference and in the document Drug Facts and Comparisons (54th edition, 2,000), pages 869-872 and. KU47; the aforementioned pages of which are incorporated herein by reference. Mixtures of serotonin receptor antagonists (5HT3) can also be used.

I. Serotonin Receptor Agonist (5HT) A safe and effective amount of a serotonin receptor agonist (5HT4) can be added to the compositions of the subject invention. Suitable serotonin receptor (5HT4) agonists include, but are not limited to, tegaserod, renzapride and prucalopride. The exact amount of serotonin receptor agonists (5HT4) to be used in the compositions will depend on the particular serotonin receptor (5HT4) antagonist used since such agents vary widely in potency. Tegaserod is a particular serotonin receptor agonist (5HT4) which accelerates orocecal transit (without effect on gastric emptying) and tends to enhance colonic transit. 12 mg / day of tegaserod shows to result in effective relief of unacceptable bowel symptoms. Prucalopride is a total serotonin (5HT4) receptor agonist which accelerates gastric, small bowel and colonic transit in functional constipation. Up to 4 mg / day, particularly 2-4 mg / day, of prucalopride sample results in effective relief of unacceptable bowel symptoms. Renzapride possesses both serotonin receptor agonist (5HT4) and serotonin receptor antagonist (5HT3), providing increased gastric emptying and reduced gastrointestinal transit time. Mixtures of the serotonin receptor agonists (5HT4) above can also be used. Mixtures of any of the aforementioned pharmaceutical compounds can also be used.

J. Selective Serotonin Reuptake Inhibitors A safe and effective amount of a selective serotonin reuptake inhibitor can be added to the compositions of the subject invention. Suitable selective serotonin reuptake inhibitors include, but are not limited to, fluoxetine, fluvofalmin, paroxetine, and sertraline. The exact amount of the selective serotonin reuptake inhibitors to be used in the compositions will depend on the selective selective serotonin reuptake inhibitor used since such agents vary widely in potency. A more complete description of the various selective serotonin reuptake inhibitors, including effective amounts thereof for use in unit dose compositions of the present invention can be found in the Drug Facts and Comparisons document (54th edition, 2,000) , pages 918-928; the aforementioned pages of which are incorporated herein by reference. Mixtures of the above selective serotonin reuptake inhibitors can also be used. Additional dosing information concerning the assets disclosed is summarized in the following table: Generic Name Usual Forces and Dosage Forms Suitable Dosages for Adults (Brand Names) Foam Mass Laxatives Polycarbophil Calcium 625 mg tablets 1-6 g / day as providing 500 polycarbophil in divided doses of polycarbophil mg (Konsyl Fiber) Methylcellulose 2 g / Tbsp of oral powder 4-6 g / day in divided doses (Citrucel) Psyllium 3.4 g / tsp or 3.4 g / Tbsp of 2.5-30 g / day in oral powder dose; wafer of 1.7 g divided (Metamucil) Antidiarrheals (opiate and anticholinergic agents) Granisetron 1 mg tablets (Kytril) Ondansetron Tablets 4, 8 mg 4 mg three times (Zofran) daily Inhibitors of Gastric Secretion Octreotide 50, 100, 200, 500, 1, 000 pg / ml of sterile solution for subcutaneous or intravenous injection (Sandostatin); 10, 20, 30 mg of sterile suspension for intramuscular injection (Sandostatin depot LAR) Vehicles In accordance with the practices of the present invention, the gastrointestinal compositions can be administered in admixture with suitable pharmaceutical diluents, carriers or other excipients (collectively referred to as "carrier" materials) selected suitably with respect to the desired route of administration and pharmaceutical practices. conventional The gastrointestinal compositions of the present invention are typically mixed with a pharmaceutically acceptable carrier. This vehicle can be a solid or liquid and the type is usually chosen based on the type of administration used. The active ingredients can be co-administered in the form of a tablet or capsule, liposome, and an agglomerated powder or in a liquid form. The capsule or tablets can be easily formulated and manufactured easily swallowed or chewed; other solid forms include granules, and powder masses. The tablets may contain suitable binding agents, and fusion agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations. reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and fusion agents. Oral dosage forms optionally contain flavoring and coloring agents. Examples of suitable tablet or capsule ingredients, including but not limited to, oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol and the like. In addition, when desired or necessary, suitable binding agents, lubricants, disintegrating agents and coloring agents may be incorporated into the mixture. Suitable binding agents include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as gum arabic, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrating agents include, in limitation, starch, methylcellulose, agar, bentonite, guar gum, etc. Of course, additionally, the compositions of the present invention can be formulated in sustained release form to provide the rate of controlled release of any one or more of the components to optimize the therapeutic effects, ie, analgesia, relaxation of the skeletal muscle, etc., while minimizing undesirable side effects. Suitable dosage forms for sustained release include layered tablets containing layers of various disintegration rates or controlled release polymer matrices impregnated with the active components and molded into a tablet or capsules containing such impregnated or encapsulated porous polymer matrices. In a similar way, injectable dosage units can be used to carry out intravenous, intramuscular or subcutaneous administration and, for such parenteral administration, suitable sterile aqueous or non-aqueous solutions or suspensions, optionally containing appropriate solutes to perform isotonicity, will be employed. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms of the present invention are described in U.S. Pat. 3,903,297 assigned to Robert, published September 2, 1975, incorporated herein by reference in its entirety. The techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & amp;; Rodees, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd edition (1976), each of which are incorporated herein by reference in its entirety. The gastrointestinal compositions of the present invention can also be formulated and administered by other methods known to administer gastrointestinal active. For example, the composition can be adapted for topical administration in the form of a rectal preparation such as a rectal cream, gel, ointment, or suppository.

Treatment Procedure The treatment procedure can be any suitable procedure which is effective in the treatment of the particular type of lower gastrointestinal tract disorder being treated. The treatment can be oral, rectal, parenteral, intravenous administration or injection. The procedure for applying an effective amount also varies depending on the gastrointestinal disorder being treated. It is believed that oral treatment with a tablet, capsule or liquid will be the method of administering the compounds to preferred warm-blooded mammals. The method of treating viral infections can also be by rectal, parenteral, or intravenous administration. The current time and dosage will depend on the type of lower gastrointestinal tract disorder being treated and the desired blood levels. In accordance with the practices of the present invention, the gastrointestinal compositions can be administered in admixture with suitable pharmaceutical diluents, carriers or other excipients (collectively referred to as "carrier" materials) selected suitably with respect to the desired route of administration and conventional pharmaceutical practices. . The gastrointestinal compositions of the present invention are typically admixed with a pharmaceutically acceptable carrier. This vehicle can be a solid or liquid and the type is usually chosen based on the type of administration being used. The active ingredients can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. The capsule or tablets can be easily formulated and can be easily manufactured for swallowing or chewing; other solid forms include granules, and powder masses. The tablets may contain suitable binding agents, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, fats and oils pharmaceutically acceptable, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and Effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and fusion agents. Oral dosage forms optionally contain flavoring and coloring agents. Examples of ingredients suitable for tablet or capsule form of administration, include but are not limited to, inert non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol and similar. In addition, when desired or necessary, suitable binding agents, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binding agents include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as gum arabic, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrating agents include, in limitation, starch, methylcellulose, agar, bentonite, guar gum, etc. Of course, additionally, the compositions of the present invention can be formulated in sustained release form to provide the rate of controlled release of any one or more of the components to optimize the therapeutic effects, that is, analgesia, skeletal muscle relaxation, etc., while minimizing undesirable side effects. Suitable dosage forms for sustained release include layered tablets containing layers of various disintegration rates or controlled release polymer matrices impregnated with the active components and molded into a tablet or capsules containing such impregnated or encapsulated porous polymer matrices. Similarly, injectable dosage units can be used to carry out intravenous, intramuscular or subcutaneous administration and, for such parenteral administration, suitable sterile aqueous or non-aqueous solutions or suspensions, optionally containing appropriate solutes to perform isotonicity, will be employed. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms of the present invention are described in U.S. Pat. 3,903,297 assigned to Robert, published September 2, 1975, incorporated herein by reference in its entirety. The techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & amp;; Rodees, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd edition (1976), each of which are incorporated herein by reference in its entirety. The gastrointestinal compositions of the present invention can also be formulated and administered by other methods known to administer gastrointestinal active. For example, the composition can be adapted for topical administration in the form of a rectal preparation such as a rectal cream, gel, ointment, or suppository.

Treatment Procedure The treatment procedure can be any suitable procedure which is effective in the treatment of the particular type of lower gastrointestinal tract disorder being treated. The treatment can be oral, rectal, parenteral, intravenous administration or injection. The procedure for applying an effective amount also varies depending on the gastrointestinal disorder being treated. It is believed that oral treatment with a tablet, capsule or liquid will be the method of administering the compounds to preferred warm-blooded mammals. The method of treating viral infections can also be by rectal, parenteral, or intravenous administration. The current time and dosage will depend on the type of lower gastrointestinal tract disorder being treated and the desired blood levels.

EXAMPLES The compositions in the following specific embodiments illustrated the gastrointestinal compositions of the present invention, but are not intended to be limiting thereof. Other modifications may be undertaken by the skilled artisan without departing from the spirit and scope of this invention. All the specified compositions can be prepared by conventional formulation and mixing techniques. The amounts of the component are listed as percentages by weight and exclude secondary materials such as diluents, bulking agents, and so on. The formulations listed, therefore, comprise the listed components and any secondary materials associated with such components.

EXAMPLE I The following is an example of a gelatin capsule composition of the present invention. The capsule is formed by combining and mixing the ingredients of each column using conventional technology and transferring the mixture to a gelatin capsule of appropriate size (eg, size # 2) for oral administration.

Ingredient% D / p Gabapentin 20,000 Trimebutin 20,000 Lactose NF1 5,000 Tricalcium Phosphate 2 55,000 1 Lactose NF - Lactose Monohydrate, Amresco Inc 2 Tricalcium Phosphate - American International Chemical Inc.

EXAMPLE II The following is an example of a rectal ointment of the present invention.

Beeswax, Bleached supplied by Strahl & Pitsch Inc. 2 White Petrolate supplied by Winco Corporation.

In a suitable beaker equipped with a heat source and a cover or cap to seal the beaker, the white wax and the petrolatum are added and heated by mixing at a melting temperature of between 85-90 ° C using a turbine blade agitator suitable. Gabapentin and trimebutine are slowly added to the molten petrolatum mixture. The mixture is cooled to a temperature of about 60 degrees C and then poured into a suitable container. The rectal ointment is applied in an appropriate amount, eg, two four grams) to the rectal area.

EXAMPLE III The following is an example of a sterile liquid composition of the present invention.

Supplied by Universal Preserv-A-Chem, Inc.

In a suitable beaker, equipped with a suitable turbine agitator, water is added for injection. While moderate agitation is provided, the remaining ingredients are added and then mixed with the water. The mixture is stirred until a homogeneous, clear solution is formed. The solution is filtered, aseptically, through a 0.22 micron filter in a sterile container suitable for filling of vials. The solution is then transferred aseptically to sterile vials of appropriate size and sealed. The injectable is administered hypodermically.

EXAMPLE IV The following is an example of an oral solution of the present invention. The solution is formed by combining and mixing the ingredients of each column using conventional technology and transferring the mixture to suitable containers (e.g., HPDE or brown glass). The oral solution is administered orally at dosage amounts of approximately 5 ml.

Ethanol 190 USP, Grain Processing Corporation Having described the invention as above, the content of the following claims is declared as property.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A composition for treating or preventing gastrointestinal disorders, consisting of: a) a safe and effective amount of a GABA analog of the formula selected from the group consisting of: R3 R2 I I H2NCHCCH2COOH I R. and mixtures thereof; and b) a safe and effective amount of an amino ether oxide and / or an ester oxide having the formula: wherein: R1 is a lower alkyl, F and R3 which are the same or different, are hydrogen or lower alkyl, R4 is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted by substituents which are identical or different, halogen or lower alkoxy, R5 is an optionally substituted phenyl radical of monosubstituted to trisubstituted by substituents which are identical or different, halogens, lower alkyl, lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical, Q is -O- or -COO -, n is equal to zero, 1 or 2, m and q are independently of each other, equal to zero or 1, p is an integer that varies between 0 and 9.

2. The composition according to claim 1, characterized in that it is additionally constituted by an active selected from the group constituted by anti-inflammatory agents, laxatives, antidiarrheals, antibiotics, anti-ulcers, inhibitors of gastric secretion , peristaltic stimulants, serotonin receptor antagonists (5HT3), serotonin receptor agonists (5HT4), selective serotonin reuptake inhibitors and mixtures thereof.

3. The composition according to claim 2, further characterized in that a) the serotonin receptor agonist (5HT4) is selected from the group consisting of tegaserod, prucalopride, and mixtures thereof; b) the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, fluvofalmin, paroxetine, and sertraline, and mixtures thereof; c) the laxative is selected from the group consisting of methylcellulose, sodium carboxymethylcellulose, malt soup extract, polyacrylic resins, plantago seeds, dioctyl calcium sulfosuccinate, dioctyl sodium sulfosuccinate, mineral oil, magnesium citrate, magnesium hydroxide, magnesium sulfate, dibasic sodium phosphate, monobasic sodium phosphate, sodium biphosphate, glycerin, anthraquinones diphenylmethane (such as bisacodyl and phenophthalein), castor oil and mixtures thereof; d) the antidiarrheal is selected from the group consisting of natural opiates, synthetic opiates, anticholinergics, acetyltannic acid, albumin tannate, alcofanone, aluminum salicylates, catechin, lidamidine, mebiquine, trillium, urazine and mixtures thereof; e) the antiulcerative is selected from the group consisting of aluminum acetoglutamide complex, zinc salt of e-acetamidocaproic acid, acetoxolone, arbaprostyl, benexate hydrochloride, bismuth subcitrate (dried), carbenoxolone, cetraxate, cimetidine, emprostilo, esaprazole , famotidine, ftaxilida, gefarnate, guaiazulene, irsogladine, nizatidine, omeprazole, ornoprostilo,? -orinazol, pifamina, piranzepina, plaunotol, ranitidine, rioprostil, rosaprostol, rotraxate, roxatidine acetate, sofalcona, spizofurona, sucralfate, teneprona, Trimoprostil, tritiozina , troxipide, zolimidine and mixtures thereof; f) the gastric secretion inhibitor is selected from the group consisting of enterogastron, octreotide and mixtures thereof; g) the peristaltic stimulant is selected from the group consisting of meclopromide, cisapride, domperidone and mixtures thereof; h) the serotonin receptor antagonist (5HT3) is selected from the group consisting of renzapride, cilansetron, ondansetron, alosetron and mixtures thereof; i) the antibiotic is selected from the group consisting of nitroimidazole antibiotics, tetracyclines, penicillins, cephalosporins, carbopenems, aminoglycosides, macrolide antibiotics, lincosamide antibiotics, 4-quinolones, rifamycins, nitrofurantoin and 10- (1-h idroxyethyl) -11-oxo-1-azatricyclo [7.2.0.0.3.8] undec-2-ene- derivatives 2-carboxylic acid and mixtures thereof.

4. The composition according to claim 1, further characterized in that it is in the form of a tablet, capsule, microcapsule, suspension, solution, injectable, rectal suppository, rectal cream, rectal ointment, rectal gel.

5. The composition according to claim 1, further characterized in that the amino ether oxide and / or an ester oxide is selected from the group consisting of trimebutine, fedotozin and mixtures thereof.

6. - The composition according to claim 3, further characterized in that the laxative is a mass-forming laxative.

7. The composition according to claim 6, further characterized in that the laxative is selected from the group consisting of polycarbophil, calcium polycarbophil and mixtures thereof.

8. The composition according to claim 1, further characterized in that it is in the form of a tablet, capsule, microcapsule, suspension, solution, injectable, rectal suppository, rectal cream, rectal ointment or rectal gel.

9. A composition for treating or preventing gastrointestinal disorders, consisting of: a GABA analog selected from the group consisting of (1-aminomethyl-3-methylcyclohexyl) acetic acid, (1-aminomethyl-3-) methylcyclopentyl) acetic acid, (1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid, 3- (1-aminoethyl) -5-methylhexanoic acid, 3-aminomethyl-5-methyl-hexanoic acid, and (S) -acid 3- (aminomethyl) -5-methylhexane and mixtures thereof; and an amino ether oxide and / or an ester oxide selected from the group consisting of trimebutine, fedotozin and mixtures thereof.

10. The use of the composition of claim 1 for preparing a medicament for treating or preventing gastrointestinal disorders in a mammal.