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
  • A61K31/13—Amines
  • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
• • 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
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

• the present invention relates to a novel, non-racemic, form of tramadol, and its use in analgesia.
• Tramadol ( ⁇ is-2-dimethylaminomethyl-l- (3-methoxy- phenyl)-l-cyclohexanol) is a chiral drug substance which is used as a high-potency analgesic agent.
• tramadol is currently marketed as the racemate only, there has been considerable interest in the physiological properties associated with its individual enantiomers, namely 1S, 2S- (-) -tramadol and lR, 2R- ⁇ +) -tramadol, the latter being shown below (1) .
• the present invention is based on the discovery that, by employing certain, non-racemic, proportions of the respective enantiomers of tramadol, the most beneficial therapeutic index, in terms of analgesic efficacy and reduction of side effects (e.g. nausea, vomiting, dizziness, constipation, sedation and others) associated with administration of the racemate, may be achieved.
• a product comprises a non-racemic mixture of the single enantiomers of tramadol as a combined preparation (kit) for simultaneous, separate or sequential use in the treatment or prevention of pain.
• a non-racemic mixture of the single enantiomers of tramadol is used in the manufacture of a medicament for the treatment or prevention of pain, and is particularly useful for the treatment of patients disposed to side effects typically associated with the administration of racemic tramadol.
• the medicament is, however, useful in treating other patient types, as discussed below.
• a product comprises a non-racemic mixture of the single enantiomers of tramadol and a pharmaceutically-acceptable carrier.
• the non-racemic mixture for use in the present invention comprises at least 60 wt.% (-) -tramadol. While enantiomerically-pure (-) -tramadol may be useful in achieving analgesia, it is preferred that (-) -tramadol be formulated with at least some (+) -tramadol, as with both enantiomers present the optimal balance between analgesic efficacy and safety is achieved.
• weight ratios of the two enantiomers lie in the range 10- 40:90-60 (+) -tramadol: (-) -tramadol (+:-), more preferred ratios lie in the range 20-40:80-60 (+:-), and the most preferred ratios lie in the range 30-40:70-60 (+:-) .
• racemic tramadol preferred non-racemic mixtures are particularly useful in the treatment of patients who are disposed to side effects typically associated with the administration of racemic tramadol.
• side effects typically observed in the administration of racemic tramadol include blurred vision, drowsiness, somnolence, hallucinations, respiratory depression, and euphoria.
• the present invention is particularly useful in treating those patients prone to nausea and vomiting. This is because, as is explained in the Example below, (-) -tramadol is believed to modulate the emetic properties of (+)- tramadol, thereby reducing the overall emetic capability of racemic tramadol. This effect can be exploited for maximum benefit using different release profiles for the different enantiomers, as is discussed below.
• the present invention is also believed to be particularly suited to the treatment of patients exhibiting abnormal CYP2D6 liver enzyme activity.
• the CYP2D6 gene encoding sparteine oxygenase is highly polymorphic, and an ever-increasing number of mutations are being identified.
• the wild-type gene is CYP2D6*1A. Any person not having the wild-type gene can be categorised as exhibiting abnormal enzyme activity. The precise nature of any particular mutation determines the degree to which a patient exhibits abnormal enzyme activity. Thus, by applying simple laboratory genetic analysis techniques it is possible to ascertain the approximate rate at which (+) -tramadol will be metabolised by a particular patient, and therefore how rapid and effective analgesia will be.
• mixtures comprising a very high proportion of (-) -tramadol may be used, for example weight ratios in the range 0-10:100-90 (+:-), with patients particularly disposed to side effects associated with racemic tramadol.
• Another option is to employ a more even balance of the two enantiomers, with the more efficacious (+) -enantiomer in excess, for instance weight ratios in the range 60-80:40-20 (+:-), typically 60-70:40- 30 (+:-).
• Such ratios may be useful in treating patients not particularly disposed to side effects associated with racemic tramadol, or where analgesic efficacy is of primary importance.
• Administration of (-) -tramadol before or at a faster rate than (+) -tramadol would, however, still be beneficial in reducing side effects.
• a further aspect of the present invention is the use of a non-racemic mixture of the single enantiomers of tramadol in the manufacture of a medicament for the prevention or treatment of migraine.
• the amount of non-racemic tramadol administered to any particular patient will depend upon the patient and the conditions for which the non-racemic tramadol is administered, and on whether non-racemic tramadol is to be used in prophylaxis or in therapy.
• Suitable amounts for administration are readily derivable by the skilled person.
• the different enantiomers of tramadol may be administered simultaneously, separately or sequentially. They may be formulated for either immediate or controlled release, or a combination of the two, or for release at different rates, or at different times.
• Preferred modes of administration release (-) -tramadol before or at a faster rate than (+) -tramadol, so as to optimise the effect of (-) -tramadol on the emetic properties of (+) -tramadol.
• situations may be envisaged, where the reverse may be required, and it is desired to administer (+)- tramadol before or at a faster rate than (-) -tramadol.
• a particularly preferred mode of administration is with (-) -tramadol in immediate release form and (+)- tramadol in controlled release form, by employing a combination of immediate and controlled release technologies, as described in WO-A-9840053 , the contents of which are incorporated herein by way of reference. It is envisaged that a dosage form of this type may be particularly beneficial in achieving rapid analgesia without the concomitant side effects associated with administration of racemic tramadol.
• a number of different types of dosage form can be envisaged for the non-racemic mixtures of the present invention, for administration by a variety of routes, e.g. oral, rectal, transdermal, nasal, ophthalmic, pormonary and injectable (subcutaneous or intravenous) .
• Suitable dosage forms include, for example, tablets, suppositories, capsules, e.g. containing multiparticulates, patches, polymer implants, aerosols, liposomes or microparticulates for injection, and any other conventional dosage form. Particularly preferred dosage forms are described in WO-A-9840053.
• a bilayered tablet is particularly preferred, including (-) -tramadol for immediate release in one layer and (+) -tramadol for controlled release in another layer.
• the results upon which the present invention are based are reported in the following Example.
• the objective was to identify the optimal range of enantiomeric ratios capable of providing the most beneficial therapeutic index, in terms of both analgesic efficacy and reduction of the nausea and vomiting associated with racemic tramadol.
• test substances Different amounts of each of the test substances were orally administered to rats, using a constant dose volume of 10 ml/kg.
• 0.1 ml of a 20% w/v suspension of Brewer's yeast in saline was injected subcutaneously into the plantar surface of the right hand paw of each rat to induce hyper-algesia.
• the left hind paw was similarly injected with 0.1 ml saline, as a control.
• Measurements of pressure tolerated were taken from the left (non-inflamed) and right (inflamed) paws 30 minutes after administration of the test substance.
• (+) -tramadol is seen to be non-emetic at doses of up to 200 mg/kg.
• (+) -tramadol induces nausea in 75% of ferrets at 50 mg/kg, while the racemate causes nausea in 25% of animals at 100 mg/kg.
• the racemate is a 50:50 mixture of the two enantiomers it is seen to induce less nausea than would be expected based on its content of (+)- enantiomer. This disparity can be explained by the ability of the (-) -enantiomer to modulate emesis associated with the (+) -enantiomer.

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• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Pain & Pain Management (AREA)
• Epidemiology (AREA)
• Gastroenterology & Hepatology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 1999
  • 1999-12-02 IL IL14277899A patent/IL142778A0/xx unknown
  • 1999-12-02 JP JP2000585200A patent/JP2002531431A/ja active Pending
  • 1999-12-02 HU HU0104420A patent/HUP0104420A2/hu unknown
  • 1999-12-02 CA CA002350635A patent/CA2350635A1/en not_active Abandoned
  • 1999-12-02 BR BR9915873-6A patent/BR9915873A/pt not_active IP Right Cessation
  • 1999-12-02 AU AU14001/00A patent/AU1400100A/en not_active Abandoned
  • 1999-12-02 CN CN99813934A patent/CN1329590A/zh active Pending
  • 1999-12-02 EP EP99973016A patent/EP1135361A1/en not_active Withdrawn
  • 1999-12-02 WO PCT/GB1999/004021 patent/WO2000032558A1/en not_active Application Discontinuation
  • 1999-12-02 PL PL99347542A patent/PL347542A1/xx not_active Application Discontinuation
  • 1999-12-02 KR KR1020017005443A patent/KR20010080364A/ko not_active Application Discontinuation
• 2001
  • 2001-06-01 NO NO20012738A patent/NO20012738L/no not_active Application Discontinuation

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