Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • A61P1/10—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
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to the treatment of functional gastrointestinal (GI) disorders, especially irritable bowel syndrome (IBS).
• IBS irritable bowel syndrome
• the present invention relates to pharmaceutical preparations containing tramadol for the treatment of such disorders and the use of tramadol in the manufacture of such preparations.
• Tramadol (2-[(Dimethylamino) methyl]-1-(3-methoxy phenyl) cyclohexanol is a non-narcotic opioid analgesic which was first described in the 1960's (see UK Patent 997399). It was first marketed in Germany in 1977 and subsequently in various countries and by 1980 a total of 34 different tramadol formulations in immediate release oral and injectable form were on the market.
• IBS is characterised by a combination of intermittent abdominal pain and diarrhoea, constipation or both; a, or the, principal symptom is pain, which often commences after eating and is relieved by defecation; abdominal distension (bloating) is common. Other symptoms include the passage of mucus and a feeling of incomplete defecation. Clinical studies have indicated that IBS is a disorder affecting the entire GI tract.
• IBS The symptoms in IBS are chronic, with remissions and relapse, which may be brought on by stress, food poisoning or changes in bowel flora produced by antibiotics, and they cause discomfort, which, depending on the severity of the disorder, can range from inconvenience to severe distress. For those with severe symptoms, IBS can cause a significant reduction in quality of life to the point where the condition is debilitating.
• IBS is not caused by structural, biochemical or infectious abnormalities. Psychological factors have been thought to be important, and more recently specific food intolerances have been implicated.
• IBS is also characterised by abnormal gut motility that is, increased or irregular muscular movement of the gut resulting in diarrhoea, constipation and spasms.
• Therapies which are currently used depending on the symptoms presented include dietary fibres i.e. ispaghula husk; antidiarrhoeals such as loperamide; osmotic laxatives; antispasmodics such as hyoscamine and dicyclomine, and dietary supervision if food intolerance is suspected.
• mebeverine which acts on smooth muscle
• results are often disappointing and this may lead to the trial of many other remedies of uncertain value, such as antidepressants mentioned above; these are thought to block the transmission of pain signals from the gut to the brain and can sometimes be effective when taken at lower doses than those administered for the treatment of depression.
• An aim of the present invention is to provide an alternative therapy for the treatment of functional GI disorder.
• tramadol in the manufacture of a medicament for the treatment of functional gastrointestinal disorders.
• tramadol is used in the manufacture of a medicament for the treatment of irritable bowel syndrome.
• tramadol is used in an amount of from 100 mg to 800 mg per day, especially 10 mg to 400 mg per day for instance 25 mg to 800 mg or 25 mg to 400 mg per day.
• Other suitable dosage ranges are 50 mg to 800 mg or 50 mg to 400 mg per day.
• a total daily dose of 10 mg to 200 mg, e.g. 25 mg to 200 mg more preferably 25 mg to 100 mg e.g. 25 mg to 50 mg or 50 mg to 100 mg will be used. If given in normal or instant releasing dosing forms this dosage will be divided equally into three, four or six doses given at intervals throughout the day. If given in controlled release form this may be given as a single dose or divided into two separate doses given at spaced intervals.
• suitable controlled release dosage forms e.g. tablets and capsules may be produced according to the methods described in European Patent Application Publications Nos. 0 624 366; 0 642 788, and U.S. Pat. No. 5,955,104, the disclosures of which are incorporated herein by reference.
• Normal release dosage forms such as tablets, capsules and drops may be produced by methods conventionally used in the art e.g. as described in Remington's Pharmaceutical Science 16th Edition 1980.
• the present invention also envisages the use of instant or rapid releasing formulations in which absorption of the drug may take place sub-lingually or transmucosally, which may e.g. be prepared by methods disclosed in U.S. Pat. No. 5,738,875.
• Tramadol can exist in four unique chemical structures; there are two geometrical isomers (which may be referred to herein as diastereoisomers or stereoisomers) cis-tramadol and trans-tramadol in each of which exist two optical isomers (enantiomers).
• Tramadol which is currently marketed is (1RS,2RS)-tramadol, the individual optical isomers of which are (1R,2R)-Tramadol or (1R,2R)-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol and (1S,2S)-tramadol or (1S,2S)-2-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol; representing the main geometric isomer, together with a small amount of a mixture of the two other optical isomers.
• the other geometric isomer which is generally found as a minor impurity in Tramadol is (1RS,2SR)-tramadol.
• the individual optical isomers of this geometric isomer are thus (1R,2S)-Tramadol or (1R,2S)-2-dimethylaminomethyl)-1-(3-methoxyphenyl) cyclohexanol and (1S,2R)-Tramadol or (1S,2R)-2-dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol.
• the present invention includes not only the use of the currently marketed form of tramadol i.e. (1RS,2RS)-Tramadol with a minor amount of (1RS,2SR)-Tramadol, but also the use of individual diastereoisomers and individual enantiomers, and where reference is made in this specification and claims to ‘tramadol’ this should be understood to mean either a mixture of geometrical isomers or individual geometrical isomers or individual enantiomers or any combination thereof, unless the context indicates otherwise.
• tramadol in the form in which it is currently marketed, that is (1RS,2RS)-Tramadol with a minor amount of (1RS,2SR)-Tramadol, or (1R,2R)-Tramadol or (1S,2S)-Tramadol.
• diastereoisomers and enantiomers are known in the art.
• the diastereoisomers can be separated using classical methods such as fractional crystallisation or chromatography in silica or alumina columns; resolution of the enantiomer may be carried out by fractional crystallisation see e.g. Elsing et al in Journal of Chromatography, 612, (1993)223 and Elsing et al. in Arch. Pharma, 324 (1991) 719, or such resolution may be carried out in known manner using chiral auxiliaries.
• compositions of tramadol for use according to the present invention are those conventionally known in the art, such as pharmaceutically acceptable acid addition salts.
• the hydrochloride salt is particularly preferred.
• colicky cramps associated with non-cardiac chest pain are ameliorated; in yet another particular aspect of the practice of the invention one or more of the symptoms associated with IBS as described above, are ameliorated or eliminated.
• the present invention also extends to the administration of tramadol in combination with other therapeutic agents, co-administered simultaneously or serially, or preferably in a combination product.
• Some therapeutic classes that might be usefully combined with tramadol for the treatment of IBS are as follows, with some examples of potentially suitable compounds:
• Antiemetics e.g. granisetron, tropisetron, prochlorperazine
• Antispasmodics and other drugs altering gut motility e.g. mebeverine hydrochloride, alverine citrate
• Gastroprokinetics and motility stimulants e.g. metoclopramide, domperidone, cisapride
• Laxatives e.g. bisacodyl, lactulose
• Analgesics e.g. paracetamol, dextropropoxyphene, dihydrocodeine
• Antidepressants e.g. amitriptyline hydrochloride, nefazodone, sertraline, venlafaxine
• Anxiolytics e.g. diazepam, buspirone, lorazepam
• Antidiarrhoeal drugs e.g. loperamide hydrochloride, codeine
• Antiflatulents e.g. activated dimethicone.
• the prime candidate is mebeverine hydrochloride, typically at a dosage of 135 mg.

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• 2001
  • 2001-03-01 DE DE60107393T patent/DE60107393T2/de not_active Expired - Lifetime
  • 2001-03-01 JP JP2001563099A patent/JP5042425B2/ja not_active Expired - Fee Related
  • 2001-03-01 EP EP01907956A patent/EP1261324B1/en not_active Expired - Lifetime
  • 2001-03-01 WO PCT/GB2001/000885 patent/WO2001064202A2/en active IP Right Grant
  • 2001-03-01 AU AU35821/01A patent/AU3582101A/en not_active Abandoned
  • 2001-03-01 US US10/220,544 patent/US20030119916A1/en not_active Abandoned
• 2006
  • 2006-05-30 US US11/443,542 patent/US8716347B2/en not_active Expired - Fee Related

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