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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61P25/20—Hypnotics; Sedatives
• • 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]
  • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• Oxcarbazepine for the Treatment of Diabetic Neuropathic Pain and the Improvement of Sleep
• the present invention relates to novel uses of the carbamazepine derivative of formula I
• the compound of formula I is known as "oxcarbazepine" (10-oxo-10,11-dihydro-5H- dibenz[b,f]azepine-5-carboxamide) and is, e.g., marketed under the brand name Trileptal ®
• Oxcarbazepine is a known anticonvulsant drug useful in the treatment of seizures of, for example, epileptic origin. Its preparation is described, e.g., in the US patent 3,642,775 and WO 01/56992, which are both herein incorporated by reference.
• an efficacious treatment of pain, in particular neuropathic pain, especially diabetic neuropathic pain, in human patients, in particular in a Caucasian patient population can be achieved by administering oxcarbazepine according to one of the dosing regimens of the present invention.
• an effect against neuropathic pain can be obtained already by using comparatively low daily doses of oxcarbazepine, e.g. 450 or 600 mg/day, i.e. at total daily doses being substantially lower than those which are commonly applied for the treatment of epilepsy.
• sleep can be improved in human patients suffering from chronic pain, in particular neuropathic pain, especially diabetic neuropathic pain, by decreasing the frequency of being awakened from sleep due to pain, decreasing the delay of getting to sleep due to pain or feeling rested after sleep by administering oxcarbazepine, especially according to one of the dosing regimens of the present invention.
• oxcarbazepine or a pharmaceutically acceptable salt thereof is administered, e.g. twice or more daily, for example two or three times daily, at a total dose in the range from about 450 mg/day to about 900 mg/day, particularly a total dose of about 550 mg/day to about 750 mg/day, especially 600 mg/day.
• the present invention relates to a method of administering oxcarbazepine to a patient, which comprises administering oxcarbazepine, or a pharmaceutically acceptable salt thereof, to a patient suffering from pain, in particular neuropathic pain, especially diabetic neuropathic pain, especially on a twice daily schedule, at a total dose in the range from about 450 mg/day to about 900 mg/day, particularly a total dose of about 550 mg/day to about 750 mg/day, especially 600 mg/day.
• the present invention relates to a method of improving sleep in human patients suffering from chronic pain, in particular neuropathic pain, especially diabetic neuropathic pain, which comprises administering oxcarbazepine or a pharmaceutically acceptable salt thereof to said patient especially on a twice daily schedule, at a total dose in the range from about 450 mg/day to about 900 mg/day, particularly a total dose of about 550 mg/day to about 750 mg/day, especially 600 mg/day.
• oxcarbazepine or a pharmaceutically acceptable salt thereof is administered, e.g. twice or more daily, for example two or three times daily, at a total dose in the range from about 900 mg/day to about 1500 mg/day, particularly a total dose of 1050 mg/day to 1350 mg/day, especially 1200 mg/day.
• the present invention relates to a method of administering oxcarbazepine to a patient, which comprises administering oxcarbazepine, or a pharmaceutically acceptable salt thereof, to a patient suffering from pain, in particular neuropathic pain, especially diabetic neuropathic pain, especially on a twice daily schedule, at a total dose in the range from about 900 mg/day to about 1500 mg/day, particularly a total dose of 1050 mg/day to 1350 mg/day, especially 1200 mg/day.
• the present invention relates to a method of improving sleep in human patients suffering from chronic pain, in particular neuropathic pain, especially diabetic neuropathic pain, which comprises administering oxcarbazepine or a pharmaceutically acceptable salt thereof to said patient especially on a twice daily schedule, at a total dose in the range from about 900 mg/day to about 1500 mg/day, particularly a total dose of 1050 mg/day to 1350 mg/day, especially 1200 mg/day.
• oxcarbazepine or a pharmaceutically acceptable salt thereof is administered, e.g. twice or more daily, for example two or three times daily, at a total dose in the range from about 1500 mg/day to about 2100 mg/day, particularly a total dose of 1650 mg/day to 1950 mg/day, especially 1800 mg/day.
• the present invention relates to a method of administering oxcarbazepine to a patient, which comprises administering oxcarbazepine, or a pharmaceutically acceptable salt thereof, to a patient suffering from pain, in particular neuropathic pain, especially diabetic neuropathic pain, especially on a twice daily schedule, at a total dose in the range from about 1500 mg/day to about 2100 mg/day, particularly a total dose of 1650 mg/day to 1950 mg/day, especially 1800 mg/day.
• the present invention relates to a method of improving sleep in human patients suffering from chronic pain, in particular neuropathic pain, especially diabetic neuropathic pain, which comprises administering oxcarbazepine or a pharmaceutically acceptable salt thereof to said patient especially on a twice daily schedule, at a total dose in the range from about 1500 mg/day to about 2100 mg/day, particularly a total dose of 1650 mg/day to 1950 mg/day, especially 1800 mg/day.
• neuropathic pain includes, but is not restricted to, pain that frequently accompanies nerve damage resulting from a range of pathologies including amputation or conditions such as diabetes, post-herpetic neuralgia or trigeminal neuralgia.
• the hyperalgesia and allodynia associated with neuropathic pain is particularly intractable and poorly treated in the clinic by treatments such as opiates or non-steroidal anti- inflammatory drugs.
• oxcarbazepine in the treatment of the above-mentioned disorders including the improvement in sleep quality can be confirmed in suitable clinical studies, e.g. those described in the Examples, e.g. applying a total daily dosage of 600 mg, 1200 mg or 1800 mg oxcarbazepine.
• suitable clinical studies are in particular randomized, double-blind, placebo-controlled, parallel studies in neuropathic pain patients.
• Fig. 1 depicts the average VAS score (y-axis) during the last week of treatment of the clinical study described in Example 1.
• Fig. 2 illustrates the average VAS score (y-axis) by week (x-axis) of the clinical study described in Example 1.
• oxcarbazepine is given twice daily on a continuous basis, alone, or during and subsequent to other therapies, for example during the treatment of diabetes.
• the single doses applied can range between 150 and 1200 mg, e.g. 300 mg, 600 mg or 900 mg, of oxcarbazepine.
• two single doses of about 900 mg are applied 6 to 12 hours apart, for example about 8 hours apart.
• Oxcarbazepine may be administered in any usual manner, e.g. orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or suspensions.
• the pharmaceutical composition is preferably a tablet, more preferably a tablet as disclosed in US 4,353,887 or, most preferably, a film-coated tablet, e.g. as described in WO 98/35681 , which publications are both incorporated herein by reference, especially the working examples.
• the pharmaceutical composition is preferably an oral suspension, more preferably an oral suspension as disclosed in WO 01/45671, which is incorporated herein by reference.
• Unit dosage forms may contain, for example, from about 2.5 mg to about 1000 mg of oxcarbazepine, e.g. 150 mg or 300 mg.
• the invention further provides the use of oxcarbazepine for the manufacture of a pharmaceutical composition for the treatment of pain, in particular neuropathic pain, especially diabetic neuropathic pain, in particular characterized in that the composition comprises between 300 and 1200 mg of oxcarbazepine.
• the invention additionally provides the use of oxcarbazepine for the manufacture of a pharmaceutical composition for the improvement of sleep in human patients suffering from chronic pain, in particular neuropathic pain, especially diabetic neuropathic pain.
• the present invention provides • a package comprising a pharmaceutical composition comprising as sole active ingredient oxcarbazepine together with instructions for improvement of sleep in human patients suffering from chronic pain, in particular neuropathic pain, especially diabetic neuropathic pain; and • a pharmaceutical composition comprising as sole active ingredient oxcarbazepine for the improvement of sleep in human patients suffering from chronic pain, in particular neuropathic pain, especially diabetic neuropathic pain.
• a package comprising a pharmaceutical composition comprising as sole active ingredient oxcarbazepine together with instructions for the treatment of pain, in particular neuropathic pain, especially diabetic neuropathic pain; and • a pharmaceutical composition comprising as sole active ingredient oxcarbazepine for the treatment of pain, in particular neuropathic pain, especially diabetic neuropathic pain.
• EXAMPLE 1 Clinical Study in Human Diabetic Neuropathic Pain Patients
• a clinical study in a Caucasian patient population a full double-blind treatment was conducted for a period of 112 days.
• Patients suffering from diabetic neuropathic pain obtained placebo or oxcarbazepine.
• VAS Visual Analog Scale
• a multicenter, placebo-controlled, double-blind, parallel-group study the efficacy of oxcarbazepine up to 1800 mg/day in patients with neuropathic pain of diabetic origin was evaluated.
• the study consisted of three phases: a pre-randomization screening phase (2 weeks); a double-blind treatment phase (18 weeks); and an open-label extension phase (52 weeks).
• the double-blind treatment phase was further divided into a titration period of 4 weeks, a maintenance period of 12 weeks, and a follow-up period of 2 weeks. Patients who met all inclusion criteria were randomized in a 1 :1 ratio to receive either study medication or placebo during double-blind treatment (16 weeks).
• oxcarbazepine or placebo was initiated at 300 mg/day, and increased 3 days later to 300 mg twice a day (600 mg/day). After this, oxcarbazepine was titrated as tolerated up to a maximum target dose of 900 mg twice a day (1800 mg/day) in increments of 300 mg every 5 days over the 4-week titration period. During the remaining 12 weeks of the study (maintenance period), oxcarbazepine treatment remained at the dose reached by day 28.
• Patient response to the following three questions from the daily sleep questionnaire were used to assess disturbances of sleep over double-blind treatment: 1) Did your pain delay you in getting to sleep last night? 2) Did your pain awaken you from sleep more than one time last night? 3) Did you feel rested after sleep this morning?
• ITT intent-to-treat
• SD standard deviation

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• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
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• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
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• 2004
  • 2004-09-02 BR BRPI0414112-1A patent/BRPI0414112A/pt not_active IP Right Cessation
  • 2004-09-02 CA CA002537060A patent/CA2537060A1/en not_active Abandoned
  • 2004-09-02 DE DE602004023861T patent/DE602004023861D1/de not_active Expired - Lifetime
  • 2004-09-02 RU RU2006110550/15A patent/RU2369393C2/ru not_active IP Right Cessation
  • 2004-09-02 US US10/570,340 patent/US20060270658A1/en not_active Abandoned
  • 2004-09-02 JP JP2006525105A patent/JP2007513056A/ja active Pending
  • 2004-09-02 SG SG200806736-5A patent/SG146631A1/en unknown
  • 2004-09-02 MX MXPA06002392A patent/MXPA06002392A/es not_active Application Discontinuation
  • 2004-09-02 WO PCT/EP2004/009797 patent/WO2005020968A2/en not_active Ceased
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• 2006
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