WO2007060491A2 - Pharmaceutical compositions comprising a sodium channel blocker in combination with a mao-b- inhibitor - Google Patents

Pharmaceutical compositions comprising a sodium channel blocker in combination with a mao-b- inhibitor Download PDF

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Publication number
WO2007060491A2
WO2007060491A2 PCT/HU2006/000102 HU2006000102W WO2007060491A2 WO 2007060491 A2 WO2007060491 A2 WO 2007060491A2 HU 2006000102 W HU2006000102 W HU 2006000102W WO 2007060491 A2 WO2007060491 A2 WO 2007060491A2
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WO
WIPO (PCT)
Prior art keywords
sodium channel
mao
inhibitor
channel blocker
pharmaceutical composition
Prior art date
Application number
PCT/HU2006/000102
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English (en)
French (fr)
Other versions
WO2007060491A3 (en
Inventor
Pál KOCSIS
István TARNAWA
Márta Thán
Károly TIHANYI
György NÉMETH
Original Assignee
Richter Gedeon Nyrt.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Richter Gedeon Nyrt. filed Critical Richter Gedeon Nyrt.
Publication of WO2007060491A2 publication Critical patent/WO2007060491A2/en
Publication of WO2007060491A3 publication Critical patent/WO2007060491A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61P25/28—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

Definitions

  • the invention relates to novel pharmaceutical combinations of voltage-gated sodium channel blockers and monoamine oxidase B (MAO-B) inhibitors with increased effect. Furthermore, the invention relates to the use of pharmaceutical combinations in Alzheimer diseases, Parkinson diseases and other neurodegenerative diseases, chronic pain, in disturbances of the motor system, in epilepsy, as well as in other therapeutic fields where the use of sodium channel blockers is acceptable.
  • MAO-B monoamine oxidase B
  • sodium channel blockers can be useful in the treatment of diseases accompanied by painful muscle spasms hindering patients in normal motion (Kocsis, P. et al. Mydeton: a centrally acting muscle relaxant drug of Gedeon Richter Ltd. Acta Pharm Hung 72: 49-61; 2002). Further possible fields of application are cerebral ischemia, hereditary channel diseases, tinnitus, migraine and drug abuse (Clare, JJ., et al. Voltage-gated sodium channels as therapeutic targets. Drug Discov. Today 5: 506-520; 2000). Several antiepileptics (phenytoin, carbamazepine) have been used for a long time.
  • the MAO-B inhibitor deprenyl (selegiline) can be applied successfully in some neurodegenerative diseases (Parkinson diseases; Youdim M.B., Finberg J.P. Pharmacological actions of 1-deprenyl (selegiline) and other selective monoamine oxidase B inhibitors. Clin. Pharmacol. Ther. 56: 725-733, 1994).
  • deprenyl prevents NMDA induced striatal cell death, and is also effective against other neurotoxins (Magyar K. Effect of selegiline against selective neurotoxins. Vopr. Med. Khim. 43: 504-514, 1997).
  • the metabolites of deprenyl also have role in this process.
  • deprenyl In addition to its MAO-B inhibitory action deprenyl has some other therapeutically advantageous effects (Magyar K., Szende B., Lengyel J., Tarczali J., Szatmary I. The neuroprotective and neuronal rescue effects of (-)-deprenyl. J. Neural. Transm. Suppl. 52: 109-123, 1998). It is known, that deprenyl increases NGF level, which contributes to its neuroprotective effect. Rasagiline, the new MAO-B inhibitor neuroprotective compound is described by the European patent EP 436492.
  • Sodium channel blockers possess several side effects a part of which is a consequence of the sodium channel blocking effect itself; e.g. cardiovascular (e.g. bradycardia, hypotonia) or CNS (e.g. ataxia, sedation) side effects.
  • cardiovascular e.g. bradycardia, hypotonia
  • CNS e.g. ataxia, sedation
  • the main object of this invention is to provide novel pharmaceutical combinations with enhanced efficaciousness that consist of a sodium channel blocker drug and a MAO-B inhibitor compound.
  • Such combinations show increased activity in the therapy of diseases which are known therapeutic targets for sodium channel blockers (i.e. chronic pain, certain disturbances of the motor system, epilepsy, drag or alcohol addiction, incontinence of faces or urine, inflammation, itching, intracranial edema, ischemia and/or subsequent damage caused by reperfusion, retinopathy caused by glaucoma) but above all in neurodegenerative disorders (Parkinson's disease, sclerosis multiplex) and possessing more favorable side effect profile than the sodium channel blocker component alone.
  • the effective therapeutic doses of both the sodium channel blockers and MAO-B inhibitors can be lowered and their clinical efficaciousness thereof can be increased, respectively.
  • Sodium channel blockers for use in the pharmaceutical compositions according to the invention are substances known to have such mechanism of action.
  • examples of such substances are lamotrigine, crobenetine, carbamazepine, phenytoin, tolperisone, eperisone, oxcarbamazepine, phosphenytoin, preferably lamotrigine, riluzole, oxcarbamazepine, phosphenytoin, or crobenetine, most preferably lamotxigine or riluzole.
  • the mixtures of such substances for use in carrying out the invention are also within the scope of the invention.
  • MAO-B inhibitors which can be used are substances known to have such mechanism of action. Examples of such substances are deprenyl and rasagiline preferably deprenyl. Optionally the mixtures of such substances for use in carrying out the invention are also within the scope of the invention.
  • compositions according to the invention can be efficient in the treatment and/or prevention of neurodegenerative diseases (e.g. ALS, HIV-related dementia, Parkinson's syndrome, Alzheimer's disease, Huntington's chorea, multiple sclerosis, prion diseases, stroke, cerebral and spinal cord injuries, cerebral ischemia), chronic pain (e. g. neuropathic pain, inflamed or rheumatic origin, trigeminal neuralgia, headache, fibromyalgia), and irritable bowel syndrome (IBS), in the treatment and prevention of the disorders of the motor system (e.g.
  • neurodegenerative diseases e.g. ALS, HIV-related dementia, Parkinson's syndrome, Alzheimer's disease, Huntington's chorea, multiple sclerosis, prion diseases, stroke, cerebral and spinal cord injuries, cerebral ischemia
  • chronic pain e. g. neuropathic pain, inflamed or rheumatic origin, trigeminal neuralgia, headache, fibromyalgia
  • spastic diseases essential tremor, dystonia, tinnitus, extrapyramidal disorders, tics
  • tics as well as in the treatment and prevention of drug or alcohol addiction, incontinence of faces and urine, inflammation, itching, intracranial edema, ischemia and/or subsequent damage caused by reperfusion or retinopathy caused by glaucoma, further in treatment and prevention of different forms of epilepsy, such as partial attacks, e.g.
  • the aforementioned diseases can successfully be treated not only by simultaneous administration of the sodium channel blockers and the MAO-B inhibitors (in which case said substances are present in two separate compositions or in a single one, i. e. in a combination) but also by sequential administration thereof, when any of the active ingredients may be administered first.
  • the active agents or the pharmaceutically acceptable derivatives thereof can be used without formulation or preferably in a form suitable for medical use, particularly for human treatment.
  • compositions may contain one or more pharmaceutically acceptable auxiliary material(s).
  • compositions may be used in oral form, parenteral form, including intravenous, subcutaneous, intradermal, intramuscular, intrathecal, rectal, topical, buccal, dermal or sublingual forms, as well as in forms suitable for inhalation.
  • Formulations suitable for oral administration can be in unit dose form, such as capsules, tablets (e. g. tablet for chewing for pediatric use), can be in powder or in granulated form, in the form of aqueous or non-aqueous solution or suspension and water-in-oil or oil-in-water emulsion form.
  • Tablets can be prepared in compressed or molded form optionally using one or more auxiliary materials.
  • Compressed tablets are prepared in an appropriate compressing machine in which the powdered or granulated active ingredients are optionally mixed with known auxiliary materials, such as binders, fillers, lubricants, disintegrators, wetting agents and flavouring substances.
  • binding agents are the syrup, acacia, gelatine, sorbitol and polyvinylpirrolidone.
  • fillers are different hydroxymethylcellulose fillers, lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or hydroxymethylcellulose.
  • lubricants are the magnesium stearate, stearic acid, talc, polyethylene glycol or silica gel.
  • disintegrators are potato starch or sodium glycolate.
  • Molded tablets can be prepared from the mixture of powdered active agents and an inert liquid solvent in an appropriate molding machine. Tablets optionally may be coated by methods known in the pharmaceutical industry. Tablets with slow or controlled release can also be prepared.
  • compositions for oral administration may also be in liquid form, such as aqueous or oily suspensions, solutions, emulsions, syrups or elixir. Such compositions may be prepared also in dry form which can be brought into the liquid form by suitable means just before treatment.
  • Said liquid formulations may contain known additives, such as suspending agents (sorbitol, syrup, methylcellulose, glucose syrup, gelatine, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or edible hydrogenated fats), emulsifying agents (lecithin, sorbitan monooleate, acacia), non-aqueous materials (oil of sweet almond, fractionated coconut oil, esters, propylene glycol, ethyl alcohol), preservatives (methyl or propyl-p-hydroxybenzoate, sorbitol) or flavouring additives.
  • suspending agents sorbitol, syrup, methylcellulose, glucose syrup, gelatine, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or edible hydrogenated fats
  • emulsifying agents lecithin, sorbitan monooleate, acacia
  • non-aqueous materials oil of sweet almond, fractionated coconut oil, esters, propylene glycol
  • compositions in suppository form may contain traditional vehicles, such as cocoa butter, solid fats, polyethylene glycol or glycerol and derivatives thereof.
  • compositions for parenteral use are aqueous or non-aqueous sterile solutions for injection and may contain antioxidants, buffers, bactericides and substances dissolved in isotonic solution.
  • the composition is then filled e. g. in ampules (one or more unit dose) or can be stored in lyophilized form.
  • compositions suitable for topical use are in the form of cream, gel, ointment or transdermal plaster.
  • intranasal compositions are sprays, dusts or drops.
  • Composition suitable for use in the treatment may be an aerosol spray containing in addition to the active ingredient a propellant, such as carbon dioxide 1,1,1-trifluorethane, 1,1,1,2,3,3,3,-heptafluorpropane or the like.
  • a propellant such as carbon dioxide 1,1,1-trifluorethane, 1,1,1,2,3,3,3,-heptafluorpropane or the like.
  • Figure 3 shows the isobologram for the interaction between lamotrigine and deprenyl.
  • the ED 50 values of lamotrigine and deprenyl to inhibit MES are plotted on the abscissa and ordinate, respectively .
  • the straight line connecting the two ED 50 values is the isobolographic line. If the experimentally determined ED 5O lies on the isobolographic line, then the drug effects are additive. If the ED 50 lies below this line, it indicates supra-additivity and when the ED 5 o lies above the isobolographic line, there is infra- additivity. ED 50 values were determined using probit analysis. The experimentally determined ED 5O values lie below the isobolographic line, thus the interaction between the two compounds seems to be clearly supra additive.
  • NMDA injected into the entorhinal cortex of animals (40 nmol NMDA in 0.5 ⁇ l buffer (PBS: 0.01M phosphate buffer, pH 7.4, 0.9% NaCl)) caused an extensive lesion in the cortex and ventral thalamus. Rats were tested in behavioral pharmacological models for 13 days after the injection. Their brains were processed histologically on day 13.
  • PBS 0.01M phosphate buffer, pH 7.4, 0.9% NaCl
  • Coronal sections were prepared from the brain after fixation.
  • the evaluation of the extent of the lesion was performed at the levels of 7.6 and 6.4 mm from bregma, using a computer-controlled planimetric system (Paxinos G, Watson G. The Rat Brain in Stereotaxic Coordinates. Academic Press, Sydney, 1982).
  • lamotrigine and deprenyl (10 mg/kg, 1 ml/kg; i.p. 60 min before the surgery; 90 min after the surgery; and twice a day during the next three days) decreased the extent of the lesion caused by NMDA.
  • Co-administration of the two drugs in the volume of 1 ml/kg resulted in a stronger protective effect.
  • NMDA+AB (6) 2.563 ⁇ 0.161 19 1.846 ⁇ 0.116 16 mean ⁇ SEM.
  • Figure 4 shows the cholin acetyl transferase positive fibers and synapses in the area of gyrus dentatus from sham operated and NMDA lesioned animals treated with a combination of deprenyl and lamotrigine.
  • NMDA treated animals Two tests were applied to asses the functional damage caused by NMDA microinjection.
  • the cubes (known objects) were exchanged (alternately in the case of each animal) to iron weights (1 kg; new object), and the time spent with exploration of the objects and the frequency of explorations were recorded again. Trainings lasted for 5 minutes. In another group of animals the first training was performed with the iron weights, which were exchanged to aluminum cubes in the second training, in an alternating manner, in order to neutralize object preference.
  • the drug administration protocol was the same described in the "Histological examination" section.
  • Figure 5 shows the effect of lamotrigine and deprenyl on the recognition of new objects.
  • NMDA treatment significantly decreased the time spent with exploring the new object.
  • deprenyl nor lamotrigine influenced significantly the exploratory time shortening effect of NMDA treatment.
  • the combined treatment with deprenyl and lamotrigine significantly increased exploratory time, which practically returned to the control value measured with sham operated animals.
  • NMDA treatment significantly decreased the time spent with exploring the new object. Neither deprenyl nor lamotrigine influenced significantly the exploratory time shortening effect of NMDA treatment.
  • the combined treatment with deprenyl and lamotrigine significantly increased exploratory time, which practically returned to the control value measured with sham operated animals.
  • the experimental device was a round basin (diameter: 153 cm) filled with water (28

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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PCT/HU2006/000102 2005-11-23 2006-11-23 Pharmaceutical compositions comprising a sodium channel blocker in combination with a mao-b- inhibitor WO2007060491A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP0501084 2005-11-23
HU0501084A HUP0501084A2 (en) 2005-11-23 2005-11-23 New pharmaceutical compositions of high effectivity

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WO2007060491A2 true WO2007060491A2 (en) 2007-05-31
WO2007060491A3 WO2007060491A3 (en) 2008-01-03

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009032273A1 (en) * 2007-09-05 2009-03-12 Teva Pharmaceutical Industries, Ltd. Method of treating glaucoma using rasagiline
US7855233B2 (en) 2009-01-23 2010-12-21 Teva Pharmaceutical Industries, Ltd. Citrate salt of Rasagiline
US20140051767A1 (en) * 2012-08-17 2014-02-20 Teva Pharmaceutical Industries, Ltd. Parenteral formulations of rasagiline

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004045515A2 (en) * 2002-11-15 2004-06-03 Teva Pharmaceutical Industries, Ltd. Use of rasagiline with or without riluzole to treat amyotrophic lateral sclerosis
WO2007054975A1 (en) * 2005-11-08 2007-05-18 Panacea Biotec Ltd Pharmaceutical compositions for the treatment of cardiovascular and other associated disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004045515A2 (en) * 2002-11-15 2004-06-03 Teva Pharmaceutical Industries, Ltd. Use of rasagiline with or without riluzole to treat amyotrophic lateral sclerosis
WO2007054975A1 (en) * 2005-11-08 2007-05-18 Panacea Biotec Ltd Pharmaceutical compositions for the treatment of cardiovascular and other associated disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WAIBEL STEFAN ET AL: "Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model" JOURNAL OF NEUROLOGY, vol. 251, no. 9, September 2004 (2004-09), pages 1080-1084, XP002445339 ISSN: 0340-5354 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009032273A1 (en) * 2007-09-05 2009-03-12 Teva Pharmaceutical Industries, Ltd. Method of treating glaucoma using rasagiline
AU2008296908B2 (en) * 2007-09-05 2014-01-09 Teva Pharmaceutical Industries, Ltd. Method of treating glaucoma using rasagiline
US7855233B2 (en) 2009-01-23 2010-12-21 Teva Pharmaceutical Industries, Ltd. Citrate salt of Rasagiline
US8080584B2 (en) 2009-01-23 2011-12-20 Teva Pharmaceuticals Industries, Ltd. Delayed release rasagiline citrate formulation
US20140051767A1 (en) * 2012-08-17 2014-02-20 Teva Pharmaceutical Industries, Ltd. Parenteral formulations of rasagiline
US9308182B2 (en) * 2012-08-17 2016-04-12 Teva Pharmaceutical Industries, Ltd. Parenteral formulations of rasagiline

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HU0501084D0 (en) 2006-01-30
WO2007060491A3 (en) 2008-01-03
HUP0501084A2 (en) 2008-05-28

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