WO2008007117A1 - Pharmaceutically acceptable salt and polymorphic forms of flupirtine maleate - Google Patents

Pharmaceutically acceptable salt and polymorphic forms of flupirtine maleate Download PDF

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Publication number
WO2008007117A1
WO2008007117A1 PCT/GB2007/002647 GB2007002647W WO2008007117A1 WO 2008007117 A1 WO2008007117 A1 WO 2008007117A1 GB 2007002647 W GB2007002647 W GB 2007002647W WO 2008007117 A1 WO2008007117 A1 WO 2008007117A1
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Prior art keywords
pain
polymorph
flupirtine maleate
disease
ray powder
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PCT/GB2007/002647
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French (fr)
Inventor
Aleksandar Danilovski
Maja Devcic
Marina Marinkovic
Ernest Mestrovic
Tina Mundofer
Iva Tunjic
Original Assignee
Pliva Hrvatska D.O.O.
Mcleish, Nicholas, Alistair, Maxwell
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Application filed by Pliva Hrvatska D.O.O., Mcleish, Nicholas, Alistair, Maxwell filed Critical Pliva Hrvatska D.O.O.
Priority to EA200970122A priority Critical patent/EA200970122A1/en
Priority to EP07766224A priority patent/EP2046749A1/en
Priority to CA002657541A priority patent/CA2657541A1/en
Priority to US12/309,260 priority patent/US8138349B2/en
Publication of WO2008007117A1 publication Critical patent/WO2008007117A1/en
Priority to US13/369,934 priority patent/US20120142743A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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 is concerned with new polymorphic forms of flupirtine maleate, processes for preparing the new polymorphic forms, pharmaceutical compositions containing them, therapeutic uses thereof and methods of treatment employing them.
  • Flupirtine maleate is chemically designated 2-amino-3-carbethoxyamino-6,4-fluorobenzylammo- pyridine maleate and can be represented by the following structural formula:
  • Flupirtine is a centrally acting non-opioid analgesic which is devoid of the typical side effects of natural or synthetic opioids, such as respiratory depression, constipation, tolerance, physical and/or psychological dependence and liability to cause addiction. It is also a muscle-relaxant. Although flupirtine does not appear to bind to any of the as yet identified NMDA receptor complex associated binding sites, it has several functional NMDA antagonistic properties. Flupirtine has also been shown to increase the expression of the protein Bcl-2, which is known to inhibit apoptosis (programmed cell death).
  • Flupirtine has a unique spectrum of pharmacological activity. Flupirtine has utility in the treatment and prevention of acute and chronic pain including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhoea, dental pain and the pain associated with degenerative and inflammatory joint disease.
  • Flupirtine also has utility in the treatment and prevention of muscular tension, muscle spasm and muscle stiffness. It is particularly useful in the treatment of back pain. Additionally, flupirtine also exerts potent cyto- and neuroprotective effects and has utility in the treatment and prevention of neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new-variant types and Batten disease.
  • Parkinson's disease dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new-variant types and Batten disease.
  • Flupirtine also has utility in the treatment and prevention of diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma and retinitis pigmentosa.
  • Flupirtine also has utility in the treatment and prevention of myocardial ischaemia and infarction, cerebral ischaemia and infarction, shock, tinnitus and hepatitis.
  • EP 0 977 736 describes a process for preparing pure flupirtine maleate in crystalline form A.
  • European Journal of Pharmaceutics and Biopharmaceutics 46 (1998) 329-337 describes crystallizates of flupirtine maleate obtained from isopropanol - these were designated as forms A and B and an isopropanol solvate form is also described, XRPD, polarization microscopy and thermoanalysis data is presented.
  • In Scientia Pharmaceutica (Sci. Pharm.) 58, 55-67 (1990) is presented differential scanning calorimetry and IR spectra data for two forms of flupirtine maleate - which they designate as Modification I and Modification II.
  • Modification I is said to have a m.p. of 170-178 0 C
  • Modification II is said to have a m.p. of 154-162 0 C.
  • Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, solubility, dissolution rate, optical and mechanical properties, vapour pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture a drug substance and a drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of a drug product.
  • Polymorphic forms as referred to herein can include crystalline and amorphous forms as well as solvate and hydrate forms, which can be further characterised as follows: (i) Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice.
  • Solvates are crystal forms containing either stoichiometric or non-stoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate.
  • Drug substance polymorphic forms can exhibit different chemical, physical and mechanical properties as referred to above, including aqueous solubility and dissolution rate, hygroscopicity, particle shape, density, flowability, and compactibility, which in turn may affect processing of the drug substance and/or manufacturing of the drug product.
  • Polymorphs can also exhibit different stabilities. The most stable polymorphic form of a drug substance is often chosen during drug development based on the minimal potential for conversion to another polymorphic form and on its greater chemical stability. However, a meta-stable form can alternatively be chosen for various reasons, including better bioavailability.
  • polymorphic forms of the pharmaceutically acceptable salt of flupirtine, flupirtine maleate with advantageous properties.
  • certain polymorphic forms of flupirtine maleate exhibit beneficial properties and, in particular, provide advantages over commercially available flupirtine maleate. The advantages are selected from, depending upon the form, increased physical stability, improved dissolution, improved morphology, improved properties when formulated and improved properties during storage.
  • polymorphic forms V, W, X 5 Y and Z of flupirtine maleate More particularly, there is provided by the present invention polymorphic forms V, W, X 5 Y and Z of flupirtine maleate.
  • the crystalline structure of polymorph V of flupirtine maleate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as is shown in Figure 1.
  • Polymorph V of flupirtine maleate according to the present invention is further characterised as having characteristic X-ray powder diffraction peaks (2 ⁇ ) selected from one or more of the following: 6.5 ⁇ 0.2°, 9.3+0.2°, 13.4+0.2°, 18.6+0.2° and 20.1 ⁇ 0.2°.
  • Further X-ray powder diffraction peaks (2 ⁇ ) associated with polymorph V of flupirtine maleate according to the present invention are selected from one or more of the following: 4.4 ⁇ 0.2°, 12.4+0.2°, 12.8+0.2°, 15.6 ⁇ 0.2° and 22.2 ⁇ 0.2°.
  • Polymorph V of flupirtine maleate according to the present invention is further characterised by a typical differential scanning calorimetry (DSC) thermogram as is shown in Figure 2.
  • DSC differential scanning calorimetry
  • Polymorph V of flupirtine maleate has a characteristic DSC endotherm in the range of 98-110 °C and in addition, has a melting endotherm of 180°C ⁇ 1 0 C.
  • the crystalline structure of polymorph W of flupirtine maleate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as is shown in Figure 3.
  • Polymorph W of flupirtine maleate according to the present invention is further characterised as having characteristic X-ray powder diffraction peaks (20) selected from one or more of the following: 5.3+0.2°, 7.9 ⁇ 0.2°, 13.0+0.2°, 18.7 ⁇ 0.2° and 20.1+0.2°. Further peaks (2 ⁇ ) associated with polymorph W of fiupirtine maleate according to the present invention are selected from one or more of the following: 6.5 ⁇ 0.2°, 9.2 ⁇ 0.2°, 10.9+0.2°, 13.4+0.2° and 15.8+0.2°.
  • Polymorph W of flupirtine maleate according to the present invention is further characterised by a typical differential scanning calorimetry (DSC) thermogram as shown in Figure 4.
  • Polymorph W of flupirtine maleate has a characteristic melting endotherm at about 180°C +1°C.
  • the crystalline structure of polymorph X of flupirtine maleate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as is shown in Figure 5.
  • Polymorph X of flupirtine maleate according to the present invention is further characterised as having characteristic X-ray powder diffraction peaks (2 ⁇ ) selected from one or more of the following: 5.8J:0.2 o , 13.3 ⁇ 0.2°, 19.4jH).2 o , 20.6j;0.2 o and 24.2J:0.2 o . Further peaks (2 ⁇ ) associated with polymorph X of flupirtine maleate according to the present invention are selected from one or more of the following: 6.6JO.2°, 17.3j+0.2°, 23.0_ ⁇ 0.2°, 24.2 jH).2 o and 26.5_ ⁇ 0.2°.
  • Polymorph X of flupirtine maleate according to the present invention is further characterised by a typical differential scanning calorimetry (DSC) thermogram as is shown in Figure 6.
  • DSC differential scanning calorimetry
  • Polymorph X of flupirtine maleate has a characteristic DSC enotherm in the range of 50-75 °C and, in addition, a melting endotherm at 179°C ⁇ 1°C
  • the crystalline structure of polymorph Y of flupirtine maleate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as is shown in Figure 7.
  • Polymorph Y of flupirtine maleate according to the present invention is further characterised as having characteristic X-ray powder diffraction peaks (2 ⁇ ) selected from one or more of the following: 8.0J:0.2 o , 10.0_ ⁇ 0.2°, 12.9j;0.2 o , 18.0.+0.2 0 and 19.5j;0.2 o .
  • Further X-ray powder diffraction peaks (2 ⁇ ) associated with polymorph Y of flupirtine maleate according to the present invention are selected from one or more of the following: 7.0_ ⁇ 0.2°, 7.5_ ⁇ 0.2°, 13.9 . +0.2 0 , 16.8_J;0.2 o and 25.8_+0.2°.
  • Polymorph Y of flupirtine maleate according to the present invention is further characterised by a typical differential scanning calorimetry (DSC) thermogram as shown in Figure 8.
  • DSC differential scanning calorimetry
  • Polymorph Y of flupirtine maleate has a characteristic DSC endotherm at 110°C+l°C and, in addition, at 119°C+1°C and, in addition, a characteristic exotherm at 134°C ⁇ 1°C and, in addition, this is followed by degradation.
  • polymorph Z of flupirtine maleate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as is shown in Figure 9.
  • Polymorph Z of flupirtine maleate according to the present invention is further characterised as having characteristic X-ray powder diffraction peaks (2 ⁇ ) selected from one or more of the following: 7.6_ ⁇ 0.2°, 9.9_+0.2°, 17.9 . +O.2 0 and 19.8_ ⁇ 0.2°.
  • peaks (2 ⁇ ) associated with polymorph Z of flupirtine maleate according to the present invention are selected from one or more of the following: 5.1JiO .2°, 6.9jH).2 o , 12.8_ ⁇ 0.2° and 22.2 ⁇ 0.2°.
  • Polymorph Z of flupirtine maleate according to the present invention is further characterised by a typical differential scanning calorimetry (DSC) thermogram as shown in Figure 10.
  • DSC differential scanning calorimetry
  • Polymorph Z of flupirtine maleate has a characteristic DSC endotherm at 108°C ⁇ l°C and, in addition, a further DSC endotherm at 133°C ⁇ 1°C and, in addition, a melting endotherm of 167 0 CfI 0 C.
  • a polymorphic form of flupirtine maleate substantially as hereinbefore described is formed by solvent crystallisation.
  • Polymorphic forms of flupirtine maleate are centrally acting non-opioid analgesics which are devoid of the typical side effects of natural or synthetic opioids, such as respiratory depression, constipation, tolerance, physical and/or psychological dependence and liability to cause addiction. They are also muscle-relaxants. They have functional NMDA antagonistic properties. They also increase the expression of the protein Bcl-2, which is known to inhibit apoptosis.
  • the polymorphic forms of flupirtine maleate have a unique spectrum of pharmacological activity. They have utility in the treatment and prevention of acute and chronic pain including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhoea, dental pain and the pain associated with degenerative and inflammatory joint disease.
  • the polymorphic forms of flupirtine maleate exert potent cyto- and neuroprotective effects and have utility in the treatment and prevention of neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new- variant types and Batten disease.
  • neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new- variant types and Batten disease.
  • the present invention further provides, therefore, pharmaceutical compositions comprising a therapeutically effective dose of a polymorphic form of flupirtine maleate according to the invention, together with a pharmaceutically acceptable carrier, diluent or excipient therefor. Excipients are chosen according to the pharmaceutical form and the desired mode of administration.
  • therapeutically effective amount means an amount of a polymorphic form of flupirtine maleate according to the invention, which is capable of preventing, ameliorating or eliminating a disease state for which administration of a centrally acting non-opioid analgesics, a muscle-relaxant, a functional NMDA antagonist or a substance that increases the expression of the protein Bcl-2 is indicated.
  • pharmaceutically acceptable it is meant that the carrier, diluent or excipient is compatible with a polymorphic form of flupirtine maleate according to the invention, and not deleterious to a recipient thereof.
  • a polymorphic form of flupirtine maleate according to the present invention is administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
  • the appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
  • a polymorphic form of flupirtine maleate according to the present invention can be used in creams, ointments or lotions. Oral administration is preferred.
  • the dose of a polymorphic form of flupirtine maleate according to the present invention can vary between 0.01 and 50 mg per kg of body weight per day.
  • Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of a polymorphic form of flupirtine maleate according to the present invention in combination with a pharmaceutical carrier.
  • This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.
  • a polymorphic form of flupirtine maleate according to the present invention is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
  • a preparation in the form of gelatin capsules can be obtained by mixing a polymorphic form of flupirtine maleate according to the present invention with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
  • a preparation in the form of a syrup or elixir or for administration in the form of drops can contain a polymorphic form of flupirtine maleate according to the present invention typically in conjunction with a sweetener, which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavouring agent and an appropriate colour.
  • a sweetener which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavouring agent and an appropriate colour.
  • Water-dispersible granules or powders can contain a polymorphic form of flupirtine maleate according to the present invention mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
  • Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example polyethylene glycols.
  • Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
  • a polymorphic form of flupirtine maleate according to the present invention can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
  • the present invention further provides a polymorphic form of flupirtine maleate substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a centrally acting non-opioid analgesic, a muscle-relaxant, a functional NMDA antagonist and/or an apoptosis inhibitor.
  • the present invention provides a polymorphic form of flupirtine maleate, substantially as hereinbefore described, for use in the manufacture of a medicament for treating and preventing a number of disorders including acute and chronic pain, including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhoea, dental pain, the pain associated with degenerative and inflammatory joint disease, muscular tension, muscle spasm, muscle stiffness, back pain, neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new-variant, Batten disease, diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, myocardial ischaemia and
  • the present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of a centrally acting non-opioid analgesic, a muscle-relaxant, a functional NMDA antagonist and/or an apoptosis inhibitor in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a polymorphic form of flupirtine maleate, substantially as hereinbefore described.
  • the present invention provides a method of treating a number of disorders, including acute and chronic pain, including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhoea, dental pain, the pain associated with degenerative and inflammatory joint disease, muscular tension, muscle spasm, muscle stiffness, back pain, neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new- variant, Batten disease, diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, myocardial ischaemia and infarction, cerebral ischaemia and infarction, shock, tinnitus and hepatitis, in
  • a polymorphic form of flupirtine maleate for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a centrally acting non-opioid analgesic, a muscle-relaxant, a functional NMDA antagonist and/or an apoptosis inhibitor, wherein the polymorphic form of flupirtine maleate according to the invention, provides an enhanced therapeutic effect compared to the therapeutic effect provided by the existing polymorphic forms of flupirtine maleate.
  • the present invention also provides a corresponding method of treatment, which comprises administering to a patient a therapeutically effective amount of a polymorphic form of flupirtine maleate, substantially as hereinbefore described, so that the administered polymorphic form of flupirtine maleate according to the present invention, provides an enhanced therapeutic effect to the patient, compared to the therapeutic effect provided by corresponding administration of the existing polymorphic forms of flupirtine maleate.
  • FIG. 2 Differential Scanning Calorimetry (DSC) thermogram of flupirtine maleate polymorph V obtained by using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.
  • DSC Differential Scanning Calorimetry
  • Figure 4 Differential Scanning Calorimetry (DSC) thermogram of flupirtine maleate polymorph W obtained by using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.
  • DSC Differential Scanning Calorimetry
  • FIG. 6 Differential Scanning Calorimetry (DSC) thermogram of flupirtine maleate polymorph X obtained by using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.
  • DSC Differential Scanning Calorimetry
  • FIG. 8 Differential Scanning Calorimetry (DSC) thermogram of flupirtine maleate polymorph Y obtained by using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.
  • DSC Differential Scanning Calorimetry
  • FIG. 10 Differential Scanning Calorimetry (DSC) thermogram of flupirtine maleate polymorph Z obtained by using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.
  • DSC Differential Scanning Calorimetry
  • Flupurtine Maleate can be synthesised in accordance with the processes described in the literature, such as US595115, WO0139760 and WO9505175.

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Abstract

The present invention is concerned with new polymorphic forms of flupirtine maleate, processes for preparing the new polymorphic forms, pharmaceutical compositions containing them, therapeutic uses thereof and methods of treatment employing them.

Description

PHARMACEUTICALLY ACCEPTABLE SALT AND POLYMORPHIC FORMS OF FLUPIRTINE MALEATE
The present invention is concerned with new polymorphic forms of flupirtine maleate, processes for preparing the new polymorphic forms, pharmaceutical compositions containing them, therapeutic uses thereof and methods of treatment employing them.
Flupirtine maleate is chemically designated 2-amino-3-carbethoxyamino-6,4-fluorobenzylammo- pyridine maleate and can be represented by the following structural formula:
Figure imgf000002_0001
Flupirtine is a centrally acting non-opioid analgesic which is devoid of the typical side effects of natural or synthetic opioids, such as respiratory depression, constipation, tolerance, physical and/or psychological dependence and liability to cause addiction. It is also a muscle-relaxant. Although flupirtine does not appear to bind to any of the as yet identified NMDA receptor complex associated binding sites, it has several functional NMDA antagonistic properties. Flupirtine has also been shown to increase the expression of the protein Bcl-2, which is known to inhibit apoptosis (programmed cell death).
As a result of these many and varied activities, flupirtine has a unique spectrum of pharmacological activity. Flupirtine has utility in the treatment and prevention of acute and chronic pain including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhoea, dental pain and the pain associated with degenerative and inflammatory joint disease.
Flupirtine also has utility in the treatment and prevention of muscular tension, muscle spasm and muscle stiffness. It is particularly useful in the treatment of back pain. Additionally, flupirtine also exerts potent cyto- and neuroprotective effects and has utility in the treatment and prevention of neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new-variant types and Batten disease.
Flupirtine also has utility in the treatment and prevention of diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma and retinitis pigmentosa.
Flupirtine also has utility in the treatment and prevention of myocardial ischaemia and infarction, cerebral ischaemia and infarction, shock, tinnitus and hepatitis.
Flupirtine maleate is available under the trade mark Katadolon™.
EP 0 977 736 describes a process for preparing pure flupirtine maleate in crystalline form A. European Journal of Pharmaceutics and Biopharmaceutics 46 (1998) 329-337 describes crystallizates of flupirtine maleate obtained from isopropanol - these were designated as forms A and B and an isopropanol solvate form is also described, XRPD, polarization microscopy and thermoanalysis data is presented. In Scientia Pharmaceutica (Sci. Pharm.) 58, 55-67 (1990) is presented differential scanning calorimetry and IR spectra data for two forms of flupirtine maleate - which they designate as Modification I and Modification II. Modification I is said to have a m.p. of 170-1780C and Modification II is said to have a m.p. of 154-1620C.
Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, solubility, dissolution rate, optical and mechanical properties, vapour pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture a drug substance and a drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of a drug product.
Polymorphic forms as referred to herein can include crystalline and amorphous forms as well as solvate and hydrate forms, which can be further characterised as follows: (i) Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.
(ii) Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice.
(iii) Solvates are crystal forms containing either stoichiometric or non-stoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate.
When a drug substance exists in polymorphic forms, it is said to exhibit polymorphism.
There are a number of methods that can be used to characterise polymorphs of a drug substance. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. X-ray powder diffraction can also be used to support the existence of polymorphs. Other methods, including microscopy, thermal analysis (e.g., differential scanning calorimetry, thermal gravimetric analysis, and hot-stage microscopy), and spectroscopy (e.g., infrared (IR) and near infrared (NIR), Raman and solid-state nuclear magnetic resonance [ssNMR]) are also helpful to further characterise polymorphic forms.
Drug substance polymorphic forms can exhibit different chemical, physical and mechanical properties as referred to above, including aqueous solubility and dissolution rate, hygroscopicity, particle shape, density, flowability, and compactibility, which in turn may affect processing of the drug substance and/or manufacturing of the drug product. Polymorphs can also exhibit different stabilities. The most stable polymorphic form of a drug substance is often chosen during drug development based on the minimal potential for conversion to another polymorphic form and on its greater chemical stability. However, a meta-stable form can alternatively be chosen for various reasons, including better bioavailability.
There is now provided by the present invention, therefore, polymorphic forms of the pharmaceutically acceptable salt of flupirtine, flupirtine maleate, with advantageous properties. We have now surprisingly found that certain polymorphic forms of flupirtine maleate exhibit beneficial properties and, in particular, provide advantages over commercially available flupirtine maleate. The advantages are selected from, depending upon the form, increased physical stability, improved dissolution, improved morphology, improved properties when formulated and improved properties during storage.
More particularly, there is provided by the present invention polymorphic forms V, W, X5 Y and Z of flupirtine maleate.
The crystalline structure of polymorph V of flupirtine maleate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as is shown in Figure 1.
Polymorph V of flupirtine maleate according to the present invention is further characterised as having characteristic X-ray powder diffraction peaks (2Θ) selected from one or more of the following: 6.5±0.2°, 9.3+0.2°, 13.4+0.2°, 18.6+0.2° and 20.1±0.2°. Further X-ray powder diffraction peaks (2Θ) associated with polymorph V of flupirtine maleate according to the present invention are selected from one or more of the following: 4.4±0.2°, 12.4+0.2°, 12.8+0.2°, 15.6±0.2° and 22.2±0.2°.
Polymorph V of flupirtine maleate according to the present invention is further characterised by a typical differential scanning calorimetry (DSC) thermogram as is shown in Figure 2. Polymorph V of flupirtine maleate has a characteristic DSC endotherm in the range of 98-110 °C and in addition, has a melting endotherm of 180°C ±10C.
The crystalline structure of polymorph W of flupirtine maleate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as is shown in Figure 3.
Polymorph W of flupirtine maleate according to the present invention is further characterised as having characteristic X-ray powder diffraction peaks (20) selected from one or more of the following: 5.3+0.2°, 7.9±0.2°, 13.0+0.2°, 18.7±0.2° and 20.1+0.2°. Further peaks (2Θ) associated with polymorph W of fiupirtine maleate according to the present invention are selected from one or more of the following: 6.5±0.2°, 9.2±0.2°, 10.9+0.2°, 13.4+0.2° and 15.8+0.2°.
Polymorph W of flupirtine maleate according to the present invention is further characterised by a typical differential scanning calorimetry (DSC) thermogram as shown in Figure 4. Polymorph W of flupirtine maleate has a characteristic melting endotherm at about 180°C +1°C.
The crystalline structure of polymorph X of flupirtine maleate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as is shown in Figure 5.
Polymorph X of flupirtine maleate according to the present invention is further characterised as having characteristic X-ray powder diffraction peaks (2Θ) selected from one or more of the following: 5.8J:0.2o, 13.3 ±0.2°, 19.4jH).2o, 20.6j;0.2o and 24.2J:0.2o. Further peaks (2Θ) associated with polymorph X of flupirtine maleate according to the present invention are selected from one or more of the following: 6.6JO.2°, 17.3j+0.2°, 23.0_±0.2°, 24.2 jH).2o and 26.5_±0.2°.
Polymorph X of flupirtine maleate according to the present invention is further characterised by a typical differential scanning calorimetry (DSC) thermogram as is shown in Figure 6. Polymorph X of flupirtine maleate has a characteristic DSC enotherm in the range of 50-75 °C and, in addition, a melting endotherm at 179°C±1°C
The crystalline structure of polymorph Y of flupirtine maleate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as is shown in Figure 7.
Polymorph Y of flupirtine maleate according to the present invention is further characterised as having characteristic X-ray powder diffraction peaks (2Θ) selected from one or more of the following: 8.0J:0.2o, 10.0_±0.2°, 12.9j;0.2o, 18.0.+0.20 and 19.5j;0.2o. Further X-ray powder diffraction peaks (2Θ) associated with polymorph Y of flupirtine maleate according to the present invention are selected from one or more of the following: 7.0_±0.2°, 7.5_±0.2°, 13.9.+0.20, 16.8_J;0.2o and 25.8_+0.2°.
Polymorph Y of flupirtine maleate according to the present invention is further characterised by a typical differential scanning calorimetry (DSC) thermogram as shown in Figure 8. Polymorph Y of flupirtine maleate has a characteristic DSC endotherm at 110°C+l°C and, in addition, at 119°C+1°C and, in addition, a characteristic exotherm at 134°C±1°C and, in addition, this is followed by degradation.
The crystalline structure of polymorph Z of flupirtine maleate according to the present invention is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as is shown in Figure 9. Polymorph Z of flupirtine maleate according to the present invention is further characterised as having characteristic X-ray powder diffraction peaks (2Θ) selected from one or more of the following: 7.6_±0.2°, 9.9_+0.2°, 17.9.+O.20 and 19.8_±0.2°. Further peaks (2Θ) associated with polymorph Z of flupirtine maleate according to the present invention are selected from one or more of the following: 5.1JiO .2°, 6.9jH).2o, 12.8_±0.2° and 22.2 ±0.2°.
Polymorph Z of flupirtine maleate according to the present invention is further characterised by a typical differential scanning calorimetry (DSC) thermogram as shown in Figure 10. Polymorph Z of flupirtine maleate has a characteristic DSC endotherm at 108°C±l°C and, in addition, a further DSC endotherm at 133°C±1°C and, in addition, a melting endotherm of 1670CfI0C.
There is also provided by the present invention processes for preparing polymorphic forms of flupirtine maleate substantially as hereinbefore described.
In certain embodiments of a process as provided by the present invention a polymorphic form of flupirtine maleate substantially as hereinbefore described is formed by solvent crystallisation.
Polymorphic forms of flupirtine maleate, as provided by the present invention, are centrally acting non-opioid analgesics which are devoid of the typical side effects of natural or synthetic opioids, such as respiratory depression, constipation, tolerance, physical and/or psychological dependence and liability to cause addiction. They are also muscle-relaxants. They have functional NMDA antagonistic properties. They also increase the expression of the protein Bcl-2, which is known to inhibit apoptosis.
As a result of these many and varied activities, the polymorphic forms of flupirtine maleate, as provided by the present invention, have a unique spectrum of pharmacological activity. They have utility in the treatment and prevention of acute and chronic pain including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhoea, dental pain and the pain associated with degenerative and inflammatory joint disease.
They also have utility in the treatment and prevention of muscular tension, muscle spasm and muscle stiffness. They are particularly useful in the treatment of back pain.
Additionally, the polymorphic forms of flupirtine maleate, as provided by the present invention, exert potent cyto- and neuroprotective effects and have utility in the treatment and prevention of neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new- variant types and Batten disease.
They also have utility in the treatment and prevention of diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma and retinitis pigmentosa.
They also have utility in the treatment and prevention of myocardial ischaemia and infarction, cerebral ischaemia and infarction, shock, tinnitus and hepatitis.
The present invention further provides, therefore, pharmaceutical compositions comprising a therapeutically effective dose of a polymorphic form of flupirtine maleate according to the invention, together with a pharmaceutically acceptable carrier, diluent or excipient therefor. Excipients are chosen according to the pharmaceutical form and the desired mode of administration. As used herein, the term "therapeutically effective amount" means an amount of a polymorphic form of flupirtine maleate according to the invention, which is capable of preventing, ameliorating or eliminating a disease state for which administration of a centrally acting non-opioid analgesics, a muscle-relaxant, a functional NMDA antagonist or a substance that increases the expression of the protein Bcl-2 is indicated.
By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient is compatible with a polymorphic form of flupirtine maleate according to the invention, and not deleterious to a recipient thereof.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, a polymorphic form of flupirtine maleate according to the present invention is administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration. For topical application, a polymorphic form of flupirtine maleate according to the present invention can be used in creams, ointments or lotions. Oral administration is preferred.
To achieve the desired prophylactic or therapeutic effect, the dose of a polymorphic form of flupirtine maleate according to the present invention can vary between 0.01 and 50 mg per kg of body weight per day. Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of a polymorphic form of flupirtine maleate according to the present invention in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.
When a solid composition in the form of tablets is prepared, a polymorphic form of flupirtine maleate according to the present invention is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in the form of gelatin capsules can be obtained by mixing a polymorphic form of flupirtine maleate according to the present invention with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir or for administration in the form of drops can contain a polymorphic form of flupirtine maleate according to the present invention typically in conjunction with a sweetener, which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavouring agent and an appropriate colour.
Water-dispersible granules or powders can contain a polymorphic form of flupirtine maleate according to the present invention mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example polyethylene glycols.
Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
A polymorphic form of flupirtine maleate according to the present invention can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
There is also provided by the present invention a polymorphic form of flupirtine maleate substantially as hereinbefore described for use in therapy.
The present invention further provides a polymorphic form of flupirtine maleate substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a centrally acting non-opioid analgesic, a muscle-relaxant, a functional NMDA antagonist and/or an apoptosis inhibitor. More specifically, the present invention provides a polymorphic form of flupirtine maleate, substantially as hereinbefore described, for use in the manufacture of a medicament for treating and preventing a number of disorders including acute and chronic pain, including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhoea, dental pain, the pain associated with degenerative and inflammatory joint disease, muscular tension, muscle spasm, muscle stiffness, back pain, neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new-variant, Batten disease, diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, myocardial ischaemia and infarction, cerebral ischaemia and infarction, shock, tinnitus and hepatitis.
The present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of a centrally acting non-opioid analgesic, a muscle-relaxant, a functional NMDA antagonist and/or an apoptosis inhibitor in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a polymorphic form of flupirtine maleate, substantially as hereinbefore described. More specifically, the present invention provides a method of treating a number of disorders, including acute and chronic pain, including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhoea, dental pain, the pain associated with degenerative and inflammatory joint disease, muscular tension, muscle spasm, muscle stiffness, back pain, neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new- variant, Batten disease, diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, myocardial ischaemia and infarction, cerebral ischaemia and infarction, shock, tinnitus and hepatitis, in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a polymorphic form of flupirtine maleate, substantially as hereinbefore described.
There is also provided by the present invention a polymorphic form of flupirtine maleate, substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a centrally acting non-opioid analgesic, a muscle-relaxant, a functional NMDA antagonist and/or an apoptosis inhibitor, wherein the polymorphic form of flupirtine maleate according to the invention, provides an enhanced therapeutic effect compared to the therapeutic effect provided by the existing polymorphic forms of flupirtine maleate. The present invention also provides a corresponding method of treatment, which comprises administering to a patient a therapeutically effective amount of a polymorphic form of flupirtine maleate, substantially as hereinbefore described, so that the administered polymorphic form of flupirtine maleate according to the present invention, provides an enhanced therapeutic effect to the patient, compared to the therapeutic effect provided by corresponding administration of the existing polymorphic forms of flupirtine maleate.
The present invention can be further illustrated by the following Figures and non-limiting Examples.
With reference to the Figures, these are as follows:
Figure 1 : X-ray powder diffraction pattern of flupirtine maleate polymorph V according to the present invention obtained by using a Philips X' Pert PRO with CuKa radiation in 2Θ = 3-40 ° range
Figure 2: Differential Scanning Calorimetry (DSC) thermogram of flupirtine maleate polymorph V obtained by using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.
Figure 3 : X-ray powder diffraction pattern of flupirtine maleate polymorph W according to the present invention obtained by using a Philips X'Pert PRO with CuKa radiation in 2Θ = 3-40 ° range. Figure 4: Differential Scanning Calorimetry (DSC) thermogram of flupirtine maleate polymorph W obtained by using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.
Figure 5: X-ray powder diffraction pattern of flupirtine maleate polymorph X according to the present invention obtained by using a Philips X'Pert PRO with CvJCa radiation in 29 = 3-40 ° range.
Figure 6: Differential Scanning Calorimetry (DSC) thermogram of flupirtine maleate polymorph X obtained by using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.
Figure 7: X-ray powder diffraction pattern of flupirtine maleate polymorph Y according to the present invention obtained by using a Philips X'Pert PRO with CuKa radiation in 29 = 3-40 ° range.
Figure 8: Differential Scanning Calorimetry (DSC) thermogram of flupirtine maleate polymorph Y obtained by using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.
Figure 9: X-ray powder diffraction pattern of flupirtine maleate polymorph Z according to the present invention obtained by using a Philips X'Pert PRO with CuKa radiation in 29 = 3-40 ° range.
Figure 10: Differential Scanning Calorimetry (DSC) thermogram of flupirtine maleate polymorph Z obtained by using a DSC Pyris 1 manufactured by Perkin- Elmer. The experiment was done under a flow of nitrogen (35 ml/min) and heating rate was 10 °C/min. A standard sample pan was used.
Flupurtine Maleate can be synthesised in accordance with the processes described in the literature, such as US595115, WO0139760 and WO9505175.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.
EXAMPLES
EXAMPLE 1
Preparation of flupirtine maleate form V
250 mg of flupirtine maleate was dissolved in 35 mL of methyl acetate whilst heating. Hot solution was filtered and crystallisation of needle like crystals occurred while cooling the solution to room temperature. The product was collected by filtration and dried overnight at room temperature. 136 mg of a white crystalline product was obtained.
EXAMPLE 2
Preparation of flupirtine maleate form W
500 mg of flupirtine maleate was placed in 3 -neck round bottom flask filled with a mixture of 96% ethanol (15 mL) and dichloromethane (30 mL). The reaction mixture was refluxed for 20 minutes whilst stirring and then cooled in an ice bath to room temperature. Stirring was then continued at room temperature overnight. The product was filtered and dried overnight at room temperature. 314 mg of a white product was obtained.
EXAMPLE 3
Preparation of flupirtine maleate form X
500 mg of flupirtine maleate was dissolved in 10 mL of 96% ethanol. The solution was heated and the hot solution was filtered and added dropwise to 20 mL of hot methyl acetate. The mixture was stirred at room temperature and precipitation of a crystalline product occurred. The product was filtered. 320 mg of a white product was obtained. EXAMPLE 4
Preparation of flupirtine maleate form Y
500 mg of flupirtine maleate was placed in 3 -neck round bottom flask filled with a mixture of 96% ethanol (15 mL) and methyl benzoate (30 mL). The reaction mixture was refluxed for 20 minutes whilst stirring and then slowly cooled to room temperature. Stirring was continued at room temperature and after 3 hours crystallisation occurred. The reaction mixture was stirred for an additional 3 hours. A white product was obtained. The product was filtered and dried overnight at room temperature. 436 mg of a white product was obtained.
EXAMPLE 5
Preparation of flupirtine maleate form Z
50 mg of flupirtine maleate was dissolved in 2 mL of anhydrous methyl benzoate whilst heating. The resulting solution was placed in a closed bottle to crystallise at room temperature. The product was filtered and dried over night at room temperature. 32 mg of a white crystalline product was obtained.
XRPD analysis was carried out on Philips X'Pert PRO diffractometer using CuKαl radiation
Experimental conditions:
Figure imgf000015_0001
Figure imgf000016_0001

Claims

1. Polymorph V of flupirtine maleate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.
2. Polymorph V of flupirtine maleate characterised as having characteristic X-ray powder diffraction peaks (2Θ): 6.5±0.2°, 9.3+0.2°, 13.4+0.2°, 18.6+0.2° and 20.1+0.2°.
3. A polymorph according to claim 2, further characterised by X-ray powder diffraction peaks (2Θ) selected from one or more of the following: 4.4±0.2°, 12.4+0.2°, 12.8+0.2°, 15.6+0.2° and 22.2±0.2°.
4. Polymorph V of flupirtine maleate characterised by a differential scanning calorimetry (DSC) thermogram as shown in Figure 2.
5. A polymorph according to claim 4 having a characteristic differential scanning calorimetry (DSC) endotherm in the range of 98- 110 °C and a melting endotherm of 180oC±loC.
6. Polymorph W of flupirtine maleate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 3.
7. Polymorph W of flupirtine maleate characterised as having characteristic X-ray powder diffraction peaks (20): 5.3±0.2°, 7.9±0.2°, 13.0+0.2°, 18.7±0.2° and 20.1±0.2°.
8. A polymorph according to claim 7, further characterised by X-ray powder diffraction peaks (2Θ) selected from one or more of the following: 6.5+0.2°, 9.2+0.2°, 10.9+0.2°, 13.4+0.2° and 15.8+0.2°.
9. Polymorph W of flupirtine maleate characterised by a differential scanning calorimetry (DSC) thermogram as shown in Figure 4.
10. A polymorph according to claim 9 having a characteristic differential scanning calorimetry (DSC) melting endotherm at 180 °C±1°C.
11. Polymorph X of fhipirtine maleate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 5.
12. Polymorph X of flupirtine maleate characterised as having characteristic X-ray powder diffraction peaks (2Θ): 5.8j;0.2o, 13.3j;0.2o, 19.4 +0.2°, 20.6_±0.2° and 24.2^0.2°.
13. A polymorph according to claim 12, further characterised by X-ray powder diffraction peaks (2Θ) selected from one or more of the following: 6.6_+0.2°, 17.3 j;0.2o, 23.0.+0.20, 24.2_±0.2° and 26.5 ±0.2°.
14. Polymorph X of flupirtine maleate characterised by a differential scanning calorimetry (DSC) thermogram as shown in Figure 6.
15. A polymorph according to claim 14 having a characteristic differential scanning calorimetry (DSC) endotherm in the range of 50-75 0C and a melting endotherm of 179°C±1°C.
16. Polymorph Y of flupirtine maleate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 7.
17. Polymorph Y of flupirtine maleate characterised as having characteristic X-ray powder diffraction peaks (2Θ): 8.0±0.2°, 10.0_±0.2°, 12.9J:0.2o, 18.0j;0.2° and 19.5J:0.2o.
18. A polymorph according to claim 17, further characterised by X-ray powder diffraction peaks (2Θ) selected from one or more of the following: 7.0.±0.2o, 1.5±0.2°, 13.9.+0.20, 16.8.+O.20 and 25.8J:0.2°.
19. Polymorph Y of flupirtine maleate characterised by a differential scanning calorimetry (DSC) thermogram as shown in Figure 8.
20. A polymorph according to claim 19 having a characteristic differential scanning calorimetry (DSC) endotherms at 110°C±l°C and 119°C±FC, an exotherm at 134°C±1°C followed by degradation.
21. Polymorph Z of flupirtine maleate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 9.
22. Polymorph Z of flupirtine maleate characterised as having characteristic X-ray powder diffraction peaks (2Θ): 7.6^0.2°, 9.9±0.2°, 17.9±0.2° and 19.8j;0.2o.
23. A polymorph according to claim 22, further characterised by X-ray powder diffraction peaks (2Θ) selected from one or more of the following: 5.1 ±0.2°, 6.9±0.2°, 12.8_±0.2° and 22.2 ±0.2°.
24. Polymorph Z of flupirtine maleate characterised by a differential scanning calorimetry (DSC) thermogram as shown in Figure 10.
25. A polymorph according to claim 24 having a characteristic differential scanning calorimetry (DSC) endotherms at 108°C±l°C and 133°C±1°C and a melting endotherm of 167OC+1OC.
26. A pharmaceutical composition comprising a therapeutically effective dose of a polymorphic form of flupirtine maleate according to any of claims 1 to 25 together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
27. A polymorphic form of flupirtine maleate form according to any of claims 1 to 25, for use in therapy.
28. Use of a polymorphic form of flupirtine maleate form according to any of claims 1 to 25, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a centrally acting non-opioid analgesics, a muscle-relaxants, a functional NMDA antagonist or a substance that increases the expression of the protein Bcl-2.
29. A use according to claim 28, wherein the disease state is selected from the group consisting of acute and chronic pain, including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhoea, dental pain, the pain associated with degenerative and inflammatory joint disease, muscular tension, muscle spasm, muscle stiffness, back pain, neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new-variant, Batten disease, diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, myocardial ischaemia and infarction, cerebral ischaemia and infarction, shock, tinnitus and hepatitis.
30. Use according to claim 28 or 29, wherein the disease state is back pain.
31. Use according to claim 28 or 29 wherein the disease state is Alzheimer's disease.
32. A method of treating a disease state prevented, ameliorated or eliminated by the administration of a centrally acting non-opioid analgesics, muscle-relaxants, functional NMDA antagonist or substance that increases the expression of the protein Bcl-2, in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a polymorphic form of flupirtine maleate according to any of claims 1 to 25.
33. A method according to claim 32, wherein the disease state is selected from the group consisting of acute and chronic pain, including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhoea, dental pain, the pain associated with degenerative and inflammatory joint disease, muscular tension, muscle spasm, muscle stiffness, back pain, neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new- variant, Batten disease, diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, myocardial ischaemia and infarction, cerebral ischaemia and infarction, shock, tinnitus and hepatitis.
34. A method according to claim 32 or 33, wherein the disease state is back pain.
35. A method according to claim 32 or 33, wherein the disease state is Alzheimer's disease.
36. Use of a polymorphic form of flupirtine maleate form according to any of claims 1-25 for the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a centrally acting non-opioid analgesics, muscle- relaxants, functional NMDA antagonist or substance that increases the expression of the protein Bcl-2 is indicated, wherein the polymorphic form of flupirtine maleate form provides an enhanced therapeutic effect compared to the therapeutic effect provided by existing polymorphic forms of flupirtine maleate.
37. A use according to claim 36, wherein the disease state is selected from the group consisting of acute and chronic pain, including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headaches, post-operative pain, post-traumatic pain, burn pain, erosion pain, dysmenorrhea, dental pain, the pain associated with degenerative and inflammatory joint disease, muscular tension, muscle spasm, muscle stiffness, back pain, neurodegenerative disorders such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS related encephalopathy, Creutzfeldt- Jakob disease including classical and new-variant, Batten disease, diseases of the eye such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, myocardial ischaemia and infarction, cerebral ischaemia and infarction, shock, tinnitus and hepatitis.
38. A use according to claim 36 or 37 wherein the disease state is back pain.
39. Use according to claim 36 or 37, wherein the disease state is Alzheimer's disease.
PCT/GB2007/002647 2006-07-13 2007-07-13 Pharmaceutically acceptable salt and polymorphic forms of flupirtine maleate WO2008007117A1 (en)

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US12/309,260 US8138349B2 (en) 2006-07-13 2007-07-13 Pharmaceutically acceptable salt and polymorphic forms of flupirtine maleate
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US20110237605A1 (en) * 2010-03-26 2011-09-29 Eric Phillips Molecular Crystal of (4-(1,8-Naphthyridin-2-YL)Piperidin-1-YL)Pyrimidine Derivative

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WO2008110357A1 (en) * 2007-03-12 2008-09-18 Elbion Gmbh Method for preparing a flupirtine maleate of a crystal modification b
WO2010017343A3 (en) * 2008-08-06 2010-05-14 Bionevia Pharmaceuticals, Inc. Flupirtine hydrochloride maleic acid cocrystal
WO2012004391A1 (en) 2010-07-09 2012-01-12 K.H.S. Pharma Holding Gmbh Process for the preparation of flupirtine maleate
DE102015013478A1 (en) 2015-10-17 2017-04-20 Goethe-Universität New crystal phases of flupirtine maleate

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CN101506169A (en) 2009-08-12
EP2046749A1 (en) 2009-04-15
DE102007032612A1 (en) 2008-01-24
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CA2657541A1 (en) 2008-01-17
US20110184030A1 (en) 2011-07-28

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