EP1549302A1 - Compositions pour troubles gastro-intestinaux comportant des derives de gaba - Google Patents

Compositions pour troubles gastro-intestinaux comportant des derives de gaba

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Publication number
EP1549302A1
EP1549302A1 EP03764069A EP03764069A EP1549302A1 EP 1549302 A1 EP1549302 A1 EP 1549302A1 EP 03764069 A EP03764069 A EP 03764069A EP 03764069 A EP03764069 A EP 03764069A EP 1549302 A1 EP1549302 A1 EP 1549302A1
Authority
EP
European Patent Office
Prior art keywords
mixtures
group
compositions
acid
rectal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03764069A
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German (de)
English (en)
Inventor
Arthur Anthony Ciociola
Catherine Ann Segal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/193,640 external-priority patent/US20040010034A1/en
Priority claimed from US10/196,060 external-priority patent/US20040010035A1/en
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1549302A1 publication Critical patent/EP1549302A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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.
  • GI lower gastrointestinal
  • the primary function of the gastrointestinal tract is the absorption of ingested nutrients. This is achieved when 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 characterized by dysphagia), achalasia (an obstructive disorder in which the lower esophageal sphincter fails to relax adequately resulting in dysphagia) and noncardiac chest pain to functional bowel disorders such as the irritable bowel syndrome (DBS), non- ulcer dyspepsia, and idiopathic -constipation.
  • DBS irritable bowel syndrome
  • IBS is particularly disturbing since it involves chronic episodes of diarrhea and/or constipation for which there is no identifiable organic cause.
  • the disorder appears to result from faulty regulation in both the gastrointestinal and nervous systems.
  • the therapy includes prokinetic agents for constipation; anticholinergics, antispasmodics such as trimebutine, tricylic and serotonin reuptake inhibitor antidepressants, and sedatives for cramping pain; and opiates (such as loperamide and diphenoxylate) and cholestyramine for diarrhea.
  • prokinetic agents for constipation include anticholinergics, antispasmodics such as trimebutine, tricylic and serotonin reuptake inhibitor antidepressants, and sedatives for cramping pain; and opiates (such as loperamide and diphenoxylate) and cholestyramine for diarrhea.
  • opiates such as loperamide and diphenoxylate
  • compositions comprising a gamma- aminobutyric acid analogs in combination with amino-ether and/or ester oxides provide a more comprehensive reduction in DBS symptoms as compared to previous drug therapies.
  • an 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 comprising gamma-aminobutyric acid analogs in combination with amino-ether and/or ester oxides.
  • compositions for treating or preventing gastrointestinal disorders comprising: a) a GABA analog of the formula selected from the group consisting of:
  • R is a lower alky
  • R 2 and Rj which are the same or different are hydrogen or lower alkyl
  • R ⁇ is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted by substituents which are identical or different
  • halogen or lower alkoxy R 5 is a phenyl radical optionally monosubstituted to trisubstituted by substituents which are the same 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 one another, equal to zero or to 1
  • p is an integer ranging from 0 to 9.
  • compositions of the present invention can comprise, consist essentially of, or consist of, the essential as well as optional ingredients and components described herein.
  • “consisting essentially of” means that the composition or component may include additional ingredients, but only if the additional-ingredients -do not materially alter the basic and novel characteristics of The claimed compositions or methods.
  • a "pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effect's (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • 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 at a reasonable benefit/risk ratio within the scope of sound medical judgement.
  • the safe and effective amount may vary with the age and physical condition of the person being treated, the severity of the condition, the specific ingredients employed, and like factors.
  • gastrointestinal disorder means a disorder of the gastrointestinal tract, including the small and large intestines and the rectum, and/or symptoms usually attributed to a dysfunction of one or more of these organs, such as diarrhea, constipation and/or abdominal and lower abdominal cramping or pain. It is understood that gastro intestinal disorders include both disorders for which an organic cause (e.g. infection by a parasite) is known and disorders for which no organic cause can be ascertained, such as IBS.
  • an organic cause e.g. infection by a parasite
  • 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, cytomegalovirus infection, 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 coli 0157:H7 bacterium, a bacterium of the genus Salmonella, a bacterium of the genus Shigella, a bacterium of the genus Campylobacter, a bacterium of the species Campylobacter jejuni, and a bacterium of the genus
  • gastrointestinal compositions of the present invention including the essential and optional components thereof, are described in detail hereinafter.
  • compositions and methods of this invention utilize a safe and effective amount of a gamma-aminobutyric acid (GABA) analogs.
  • GABA gamma-aminobutyric acid
  • a GABA analog is any compound derived from or based upon gamma-aminobutyric acid. The compounds are readily available, either commercially, or by synthetic methodology well known to those skilled in the art of organic chemistry.
  • GABA analogs used in the present invention are cyclic amino acids of Formula 1.
  • R ⁇ is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof.
  • An especially useful embodiment utilizes a compound of Formula I where Ri is hydrogen and n is 5, which compound is 1 -(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin.
  • GABA analogs of Formula I wherein the cyclic ring is substituted, for example with alkyl groups such as methyl or ethyl.
  • Typical compounds include (l-aminomethyl-3-methylcyclohexyl) acetic acid, (1- aminomethyl-3-rnefhylcyclopentyl)acetic acid, and (l-aminomethyl-3,4-dimethylcyclopentyl)acetic acid.
  • Compounds and embodiments of Formula I are described in more detail in U.S. Patent 4,024,175; herein incorporated by reference in its entirety.
  • GABA analogs of Formula II are also useful in the present invention.
  • is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;
  • R 2 is hydrogen or methyl;
  • R 3 is hydrogen, methyl, or carboxyl.
  • Diastereomers and enantiomers of compounds of Formula II can be utilized in the invention.
  • An especially useful embodiment employs a compound of Formula II where R 2 and R 3 are both hydrogen, and Ri is — (CH 2 )o. -iC 4 H 9 as an (R), (S), or (R,S) isomer.
  • the percentage of the active ingredient in the foregoing 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, from 10% to 90%_by weight-
  • the basamount of GABA analog 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 subject body weight.
  • Typical doses will be from about 10 to about 5000 mg, preferably from about 20 to about 800mg, per day for an adult subject of normal weight. It is expected that common doses that might be administered could be from 100 mg three times a day up to 600 mg four times a day.
  • Useful intravenous dose is between about 5 and about 50 mg.
  • GABA analog effective amounts thereof for use in unit dose compositions of the present invention can be found in US Patents 6,127,418 and 6,1 17,908, both of which are herein incorporated by reference in their entirety.
  • compositions and methods of the present invention also comprise a safe and effective amount of an amino-ether and/or -ester oxide.
  • Amino-ether and/or -ester oxides according to the invention conform to the formula: y
  • is a lower alkyl
  • R 2 and R 3 which are the same or different are hydrogen or lower alkyl
  • Ri is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted by substituents which are identical or different, halogen or lower alkoxy
  • R 5 is a phenyl radical optionally monosubstituted to trisubstituted by substituents which are the same or different, halogen, lower alkyl.
  • a pyridyl radical or a lower alkyl radical O is -O- or -COO-
  • n is equal to zero
  • m and q are, independently of one another, equal to zero or to 1
  • p is an integer ranging from 0 to 9.
  • lower radical are meant radicals having from 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms in a straight or branched chain.
  • R 5 is alky] it is preferably methyl.
  • amino-ether oxides are halogenated, they are preferably brominated or chlorinated.
  • the invention also embraces the acid addition salts of amino-ether oxides, notably those of mineral acids, such as halohydrates, sulphates, phosphates, or organic acids such as maleates, citrates, malates, tartrates, methanesulphonates, camphosulphonates, benzoates, etc.
  • the invention further covers both racemic and optionally active forms which can be separated, particularly by forming salts with optically active acids.
  • suitable amino-ether and/or -ester oxides include trimebutine (3,4,5- trimethoxybenzoic acid 2-(dimethylamino)-2-phenylbutyl ester), fedotozine ((R)- ⁇ -ethyl-N,N- dimethyl- ⁇ -[[(3,4,5-trimethoxyphenyl) methoxyjmethyl] benzenemethanamine) and mixtures thereof.
  • Trimebutine is available under the tradenames Modulon (Canada), Debridat (Italy), Cerekinon (Japan), and Polibutin (Spain).
  • Modulon Canada
  • Debridat Italy
  • Cerekinon Japan
  • Polibutin Spain
  • Fedotozine has been administered effectively at dosages of up to 210mg daily, preferably 30 to 70 mg three times daily, and up to lOOmg intravenously daily.
  • Trimebutine has been effectively administered orally at up to 600mg/day, preferably up to 200 milligrams 3 times daily, or intramuscularly/intravenously at up to 100 milligrams every 12 hours.
  • the amino-ether and/or ester oxides are preferably administered orally at 1 -75 mg/kg, preferably 2-50 mg/kg and most preferably at 5-20 mg/kg.
  • compositions of the present invention can additionally contain: A. Anti-Inflammatory Agents
  • a safe and effective amount of an anti-inflammatory agent may be added to the compositions 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 utilized since such agents vary widely in potency.
  • a more complete description of the various NSAID's, including acceptable analgesically effective amounts thereof for use in unit dose compositions of the present invention also appears in applicants co-pending U.S. application Ser. Nos. 474,358, filed Mar. 1 1, 1983, and now U.S. Pat. No. 4.486.436. and 578,288, filed Feb. 8, 1984, now U.S. Pat. No. 4.522.826 the entire disclosures of which are incorporated herein by reference.
  • Steroidal anti-inflammatory agents including but not limited to, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate. desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichJorisone. diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide.
  • corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate.
  • desonide desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichJorisone. dif
  • fludrocortisone flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, fiucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone diacetate, fluradrenolone acetonide, - medrysone, amcinafel, - amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichJori
  • steroidal anti-inflammatory agents can also be used.
  • the preferred steroidal anti-inflammatory for use is hydrocortisone.
  • second-class of anti-inflammatory agents which is useful in the compositions includes the nonsteroidal anti-inflammatory agents.
  • the variety of compounds encompassed by this group are well-known to those skilled in the art.
  • compositions include, but are not limited to:
  • the oxicams such as piroxicam, isoxicam. tenoxicam, sudoxicam, and CP- 14,304;
  • salicylates such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal;
  • acetic acid derivatives such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac;
  • the fenamates such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids
  • the propionic acid derivatives such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, s ⁇ profen, alminoprofen, and tiaprofenic; and 6) the pyrazoles, such as phenylbutazone, oxypbenbutazone, feprazone, azapropazone, and trimethazone.
  • non-steroidal anti-inflammatory agents may also be employed, as well as the pharmologically acceptable salts and esters of these agents.
  • etofenamate a flufenamic acid derivative
  • ibuprofen naproxen
  • flufenamic acid etofenamate
  • aspirin mefenamic acid
  • -meclofenamic acid piroxicam and-felbinac are preferred; ibuprofen, naproxen, etofenamate, aspirin and flufenamic acid are most-preferred.
  • agents are useful in methods of the subject invention.
  • Such agents may suitably be obtained as an extract by suitable physical and/or chemical isolation from natural sources (e.g., plants, fungi, by-products of microorganisms).
  • natural sources e.g., plants, fungi, by-products of microorganisms.
  • candelilla wax, alpha bisabolol, aloe vera, Manjistha (extracted from plants in the genus Rubia, particularly Rubia Cordifolia), and Guggal (extracted from plants in the genus Commiphora, particularly Commiphora Mukul), kola extract, chamomile, and sea whip extract may be used.
  • Additional anti-inflammatory agents useful herein include compounds of the Licorice (the plant genus/species Glycyrrhiza glabra) family, including glycyrrhetic acid, glycyrrhizic acid, and derivatives thereof (e.g., salts and esters).
  • Suitable salts of the foregoing compounds include metal and ammonium salts.
  • Suitable esters include C 2 -C 24 saturated or unsaturated esters of the acids, preferably Cio -C 24 , more preferably C, 6 -C 24 .
  • oil soluble licorice extract examples include oil soluble licorice extract, the glycyrrhizic and glycyrrhetic acids themselves, monoammonium glycyrrhizinate, monopotassium glycyrrhizinate, dipotassium glycyrrhizinate, 1 -beta-glycyrrhetic acid, stearyl glycyrrhetinate, and 3-stearyloxy-glycyrrhetinic acid, and disodium 3-succinyloxy-beta- glycyrrhetinate.
  • Stearyl glycyrrhetinate is preferred.
  • Laxatives A safe and effective amount of a laxative may be added to the compositions of the subject invention. The exact amount of laxative to be used in the compositions will depend on the particular laxative utilized since such agents vary widely in potency. A more omplete description of the various laxatives, including acceptable laxative effective amounts thereof for use in unit dose compositions of the present invention can be found in US patent 5,516,524; herein incorporated by reference in its entirety; as well as the Handbook of Nonprescription Drugs, 12th Ed., Chapter 12, pp. 279-290 (American Pharmaceutical Association, Washington, D.C.; 2000); and Drug Facts and Comparisons (54th Ed. 2000), pp. 1 166-1 177; the cited pages of which are herein incorporated by reference.
  • Laxatives useful herein include, but are not limited to, hydrophilic derivatives of cellulose
  • a safe and effective amount of an antidiarrheal may 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 utilized since such agents vary widely in potency.
  • a more complete description of the various antidiarrheals, including acceptable antidiarrheal effective amounts thereof for use in unit dose compositions of the present invention can be found in the Handbook of Nonprescription Drugs, 12th Ed., Chapter 13, pp. 312-316 (American Pharmaceutical Association, Washington, D.C.; 2000);-and Drug Facts- and Comparisons (54th Ed. 2000), pp. 1 178-1 182; the cited pages of which are herein incorporated by reference.
  • Antidiarrheals useful herein include, but are not limited to, natural or synthetic opiates (such as difenoxin, diphenoxylate, pargoric, opium tincture, and loperamide), anticholinergics (such as belladonna alkoloids - atropine hyoscyamine, and hyosine), acetyltannic acid, albumin tannate, alkofanone, aluminum salicylates, catechin, , lidamidine, mebiquine, trillium, and uzarin. Mixtures of the above antidiarrheals can also be used.
  • natural or synthetic opiates such as difenoxin, diphenoxylate, pargoric, opium tincture, and loperamide
  • anticholinergics such as belladonna alkoloids - atropine hyoscyamine, and hyosine
  • acetyltannic acid such as album
  • a safe and effective amount of an antiulcerative may 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 utilized since such agents vary widely in potency.
  • a more complete description of the various antiulceratives, including acceptable antiulcerative effective amounts thereof for use in unit dose compositions of the present invention can be found in the Drug Facts and Comparisons (54th Ed. 2000), pp. 1 131 -1 139; the cited pages of which are herein incorporated by reference.
  • Antiulcerative useful in the present invention include, but are not limited to, aceglutamide aluminum complex, ⁇ -acetamidocaproic acid zinc salt, acetoxolone, arbaprostil, benexate hydrochloride, bismuth subcitrate sol (dried), carbenoxolone, cetraxate, cimetidine, enprostil, esaprazole, famotidine, ftaxilide, gefarnate, guaiazulene, irsogladine, izatidine, omeprazole, omoprostil, ⁇ -oryzanol, pifarnine, pirenzepine, plaunotol, ranitidine, rioprostil, rosaprostol, rotraxate, roxatidine acetate, sofalcone, spizofurone, sucralfate, teprenone, trimoprostil, thrithiozine, troxi
  • a safe and effective amount of an antibiotic may be added to the compositions of the subject invention.
  • the exact amount of the antibiotic to be used in the compositions will depend on the particular antibiotic utilized since such agents vary widely in potency.
  • a complete description of the various antibiotics, including acceptable antibiotic effective amounts thereof for use in unit dose compositions of the present invention can be found in the Drug Facts and Comparisons (54th Ed.
  • antibiotics may be used according to the invention, including for example nitroimidazole antibiotics (e.g. tinidazole or metronidazole), tetracyclines (e.g. tetracyclin, doxycyclin and minocyclin), pencillins (e.g. amoxycillin, ampicillin and mezlocillin), cephalosporins (e.g. cefachlor, cefadroxil, cephradine, cefuroxime, cefuroxime axetil, cephalexin, cefpodoxime proxetil, ceftazidime and ceftriaxone), carbopenems (e.g.
  • nitroimidazole antibiotics e.g. tinidazole or metronidazole
  • tetracyclines e.g. tetracyclin, doxycyclin and minocyclin
  • pencillins e.g. amoxycillin, ampicillin and me
  • imipenem and meropenem amino-glycosides (e.g. paromonycin), macrolide antibiotics (e.g. erythromycin, clarithromycin and azithromycin), lincosamide antibiotics (e.g. clindamycin), 4-quinolones (e.g. ofloxacin, ciprofloxacin, pefloxacin and norfloxacin), rifamycins (e.g.
  • Gastric Secretion Inhibitors A safe and effective amount of a gastric secretion inhibitor may be added to the compositions of the subject invention. Suitable gastric secretion inhibitors 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 particular gastric secretion inhibitor utilized since such agents vary widely in potency. A more complete description of the various Gastric Secretion Inhibitors, including acceptable e Gastric Secretion Inhibitor effective amounts thereof for use in unit dose compositions of the present invention can be found in the Drug Facts and Comparisons (54th Ed. 2000), pp. 352-354; the cited pages of which are herein incorporated by reference. Mixtures of the above gastric secretion inhibitors can also be used.
  • Peristaltic Stimulants A safe and effective amount of a peristaltic stimulant may be added to the compositions of the subject invention. Suitable peristaltic stimulants include, but are not limited to, dexpanthenol, metoclopromide, cisapride, and domperidone. The exact amount of peristalitc stimulants to be used in the compositions will depend on the particular peristalitc stimulant utilized since such agents vary widely in potency. A more complete description of the various, Peristaltic Stimulants including acceptable Peristaltic Stimulant effective amounts thereof for use in unit dose compositions of the present invention can be found in the Drug Facts and Comparisons (54th Ed. 2000), pp. 1 188-1 193; the cited pages of which are herein incorporated by reference. Mixtures of the above peristalitc stimulants can also be used.
  • a safe and effective amount of a serotonin (5HT 3 ) receptor antagonist may be added to the compositions of the subject invention.
  • Suitable serotonin (5HT 3 ) receptor antagonists include, but are not limited to, cilansetron, dolasetron, ondansetron and alosetron. The exact amount of serotonin
  • Serotonin (5HT 4 ) Receptor agonist A safe and effective amount of a serotonin (5HT 4 ) receptor agonist may be added to the compositions of the subject invention.
  • Suitable serotonin (5HT 4 ) receptor agonists include, but are not limited to tegaserod, renzapride and prucalopride.
  • the exact amount of serotonin (5HT 4 ) receptor agonists to be used in the compositions will depend on the particular serotonin (5HT 4 ) receptor agonist utilized since such agents vary widely in potency.
  • Tegaserod is a partial serotonin (5HT 4 ) receptor agonist which accelerates orocecal transit (without effect on gastic emptying) and tends to enhance colonic transit.
  • Prucalopride is a full serotonin (5HT 4 ) receptor agonist which accelerates gastric, small bowel and colonic transit in functional constipation. Up to 4mg/day, particularly 2-4mg/day, of prucalopride is taught to result in effective relief of untoward bowel symptoms. Renzapride possesses both serotonin (5HT 4 ) receptor agonist and serotonin (5HT 3 ) receptor antagonist activity, providing increased gastric emptying and reduced gastrintestinal transit time. Mixtures of the above serotonin (5HT ) receptor agonists can also be used. Mixtures of any of the above-mentioned pharmaceutical compounds can also be used.
  • a safe and effective amount of a selective serotonin reuptake inhibitor may be added to the compositions of the subject invention.
  • Suitable selective serotonin reuptake inhibitors include, but are not limited to, fluoxetine, fluvoxamine, paroxetine, and sertraline.
  • the exact amount of selective serotonin reuptake inhibitors to be used in the compositions will depend on the particular selective serotonin reuptake inhibitor utilized since such agents vary widely in potency.
  • a more complete description of the various selective serotonin reuptake inhibitors, including acceptable effective amounts thereof for use in unit dose compositions of the present invention can be found in the Drug Facts and Comparisons (54th Ed. 2000), pp. 918-928; the cited pages of which are herein incorporated by reference. Mixtures of the above selective serotonin reuptake inhibitors can also be used.
  • Paroxetine 10 mg/5 mL oral suspension 10-, 20-, 30-, 40-mg tablets (Paxil)
  • Octreotide 50 100, 200, 500, 1000 ⁇ g/mL sterile solution for s.c. or i.v. injection (Sandostatin);10-, 20-, 30-mg sterile suspensionfor i.m. injection (Sandostatin LAR Depot)
  • the gastrointestinal compositions may be administered in admixture with suitable pharmaceutical diluents, carriers or other excipients (collectively referred to as "carrier" materials) suitably selected with respect to the intended route of administration and conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, carriers or other excipients
  • the gastrointestinal compositions of the present invention are typically mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid and the type is generally chosen based on the type of administration being used.
  • the actives can be coadministered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders.
  • Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable 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 melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • suitable tablet or capsule form ingredients include but are 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.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated in the mixture.
  • suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • Disintegrators include, without limitation, starch7methylce]lu]ose,_agar, bentonite, guar gum, etc.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components to optimize the therapeutic effects, i.e., analgesia, skeletal muscle relaxation, etc. while minimizing undesirable side effects.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • injectable dosage units may be utilized to accomplish intravenous, intramuscular or subcutaneous administration and, for such parenteral administration, suitable sterile aqueous or non-aqueous solutions or suspensions, optionally containing appropriate solutes to effectuate isotonicity, will be employed.
  • compositions of the present invention may also be formulated and administered by other methods known for administering gastrointestinal actives.
  • the composition may be adapted for topical administration in the form of rectal preparations such as a rectal cream, gel, ointment, or suppository.
  • the method of treatment can be any suitable method which is effective in the treatment of the particular type of lower gastrointestinal disorder that is being treated.
  • Treatment may be oral, rectal, parenteral, intravenous administration or injection.
  • the method of applying an effective amount also varies depending on the lower gastrointestinal disorder being treated. It is believed that oral treatment by tablet, capsule or liquid will be the preferred method of administering the compounds to warm blooded mammals.
  • the method of treating viral infections may also be by rectal, parenteral, or intravenous administration.
  • the actual time and dosage will depend on the type of the lower gastrointestinal disorder being treated and the desired blood levels.
  • the gastrointestinal compositions may be administered in admixture with suitable pharmaceutical diluents, carriers or other excipients (collectively referred to as "carrier" materials) suitably selected with respect to the intended route of administration and conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, carriers or other excipients
  • the gastrointestinal compositions of the present invention are typically mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid and the type is generally chosen based on the type of administration being used.
  • the actives can be coadministered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable 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 melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • suitable tablet or capsule form ingredients include but are 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.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated in the mixture.
  • suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components to optimize the therapeutic effects, i.e., analgesia, skeletal muscle relaxation, etc. while minimizing undesirable side effects.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • injectable dosage units may be utilized to accomplish intravenous, intramuscular or subcutaneous administration and, for such parenteral administration, suitable sterile aqueous or non-aqueous solutions or suspensions, optionally containing appropriate solutes to effectuate isotonicity, will be employed.
  • compositions of the present invention may also be formulated and administered by other methods known for administering gastrointestinal actives.
  • the composition may be adapted for topical administration in the form of rectal preparations such as a rectal cream, gel, ointment, or suppository.
  • the method of treatment can be any suitable method which is effective in the treatment of the particular type of lower gastrointestinal disorder that is being treated.
  • Treatment may be oral, rectal, parenteral, intravenous administration or injection.
  • the method of applying an effective amount also varies depending on the lower gastrointestinal disorder being treated. It is believed that oral treatment by tablet, capsule or liquid will be the preferred method of administering the compounds to warm blooded mammals.
  • the method of treating lower gastrointestinal disorders may also be by rectal, parenteral, or intravenous administration.
  • the actual time and dosage will depend on the type of the lower gastrointestinal disorder being treated and the desired blood levels.
  • compositions in the following illustrate specific embodiments of the gastrointestinal compositions of the present invention, but are not intended to be limiting thereof. Other modifications can be undertaken by the skilled artisan without departing from the spirit and scope of this invention.
  • compositions can be prepared by conventional formulation and mixing techniques.
  • Component amounts are listed as weight percents and exclude minor materials such as diluents, filler, and so forth.
  • the listed formulations therefore, comprise the listed components and any minor materials associated with such components.
  • the capsule is formed by combining and mixing the ingredients of each column using conventional technology and transferring the mixture to an appropriate sized hard gelatin capsule (e.g., #2 size) for oral administration.
  • an appropriate sized hard gelatin capsule e.g., #2 size
  • Example II The following is an example of a rectal ointment of the present invention.
  • the rectal ointment is applied in an appropriate amount (e.g., two to four grams) to the rectal area .
  • Example III The following is an example of an sterile liquid composition of the present invention.
  • the water for injection is added. While providing moderate agitation, the remaining ingredients are then added and mixed with the water. The mixture is stirred until a homogenous, clear solution is formed.
  • the solution is filtered, aseptically, through a 0.22 micron filter into a sterile container suitable for vial filling. The solution is then aseptically transferred to appropriately sized sterile vials and sealed.
  • the injectable is administered hypodermically.
  • the solution is formed by combining and mixing the ingredients of each column using conventional technology and transferring the mixture to an appropriate containers (e.g., HDPE or brown glass).
  • the oral solution is administered orally at dosage amounts of about 5ml.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention se rapporte à des compositions et à des procédés permettant de traiter et/ou prévenir des troubles du tractus gastro-intestinal inférieur (GI) chez des patients mammifères, et plus particulièrement de soulager et/ou de prévenir les symptômes du tractus gastro-intestinal inférieur associés à ces troubles.
EP03764069A 2002-07-10 2003-06-30 Compositions pour troubles gastro-intestinaux comportant des derives de gaba Withdrawn EP1549302A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US193640 2002-07-10
US10/193,640 US20040010034A1 (en) 2002-07-10 2002-07-10 Gastrointestinal compositions
US196060 2002-07-15
US10/196,060 US20040010035A1 (en) 2002-07-15 2002-07-15 Gastrointestinal compositions
PCT/IB2003/003156 WO2004006901A1 (fr) 2002-07-10 2003-06-30 Compositions pour troubles gastro-intestinaux comportant des derives de gaba

Publications (1)

Publication Number Publication Date
EP1549302A1 true EP1549302A1 (fr) 2005-07-06

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EP (1) EP1549302A1 (fr)
JP (1) JP2005533100A (fr)
AU (1) AU2003247042A1 (fr)
BR (1) BR0312568A (fr)
CA (1) CA2491721A1 (fr)
MX (1) MXPA05000405A (fr)
WO (1) WO2004006901A1 (fr)

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KR20060087560A (ko) * 2003-09-12 2006-08-02 워너-램버트 캄파니 엘엘씨 알파-2-델타 리간드 및 ｓｓｒｉ 및/또는 ｓｎｒｉ를포함하는 우울증 및 불안 장애 치료용 조합물
US8060050B2 (en) 2004-06-04 2011-11-15 Broadcom Corporation Method and system for analog and digital RF receiver interface
ITMI20041447A1 (it) * 2004-07-20 2004-10-20 Zambon Spa Composizione farmaceutica comprendente gabapentina
CN107582521A (zh) * 2017-09-27 2018-01-16 江西省子轩科技有限公司 一种稳定性好的乙酰谷酰胺注射液及其制备方法

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FR2460919A1 (fr) * 1979-07-11 1981-01-30 Prod Synthese Ste Indle Amino-ethers oxydes, leur procede de preparation et leur application en therapeutique
US5245080A (en) * 1989-02-20 1993-09-14 Jouveinal Sa (+)-1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-N-propylamine, process for preparing it and its therapeutical use
AU8668598A (en) * 1997-08-20 1999-03-08 University Of Oklahoma, The Gaba analogs to prevent and treat gastrointestinal damage
US6127418A (en) * 1997-08-20 2000-10-03 Warner-Lambert Company GABA analogs to prevent and treat gastrointestinal damage

Non-Patent Citations (1)

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Title
See references of WO2004006901A1 *

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CA2491721A1 (fr) 2004-01-22
MXPA05000405A (es) 2005-03-23
JP2005533100A (ja) 2005-11-04
WO2004006901A1 (fr) 2004-01-22
BR0312568A (pt) 2005-05-03
AU2003247042A1 (en) 2004-02-02

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