WO2011000562A1 - Eltoprazine pour le traitement de certains troubles du mouvement - Google Patents

Eltoprazine pour le traitement de certains troubles du mouvement Download PDF

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Publication number
WO2011000562A1
WO2011000562A1 PCT/EP2010/003963 EP2010003963W WO2011000562A1 WO 2011000562 A1 WO2011000562 A1 WO 2011000562A1 EP 2010003963 W EP2010003963 W EP 2010003963W WO 2011000562 A1 WO2011000562 A1 WO 2011000562A1
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Prior art keywords
eltoprazine
day
administration
composition
treatment
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PCT/EP2010/003963
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English (en)
Inventor
Barbara Valastro
Lutz Franke
Hermann Russ
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Merz Pharma Gmbh & Co. Kgaa
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Publication of WO2011000562A1 publication Critical patent/WO2011000562A1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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

Definitions

  • the present invention relates to the efficient treatment of an individual afflicted with certain movement disorders, the instant treatment comprising administering to the individual an effective amount of eltoprazine or a pharmaceutically acceptable salt thereof.
  • This invention relates to an innovative method of treating patients afflicted with a movement disorder taken from the list of: graft-induced dyskinesia (GID), Huntington's disease, and restless leg syndrome (RLS).
  • a movement disorder taken from the list of: graft-induced dyskinesia (GID), Huntington's disease, and restless leg syndrome (RLS).
  • Eltoprazine (1-(2,3-dihydro-1 ,4-benzodioxin-8-yl)piperazine) was synthesized more than two decades ago by scientists at Duphar International Research B. V., Netherlands, and was first described in EP 0138280 (published April 24, 1985) as intermediate for the synthesis of piperazine derivatives.
  • European patent application EP 0189612 (filed December 16, 1985) disclosed for the first time the use of eltoprazine as a pharmaceutical compound.
  • Eltoprazine and related compounds were characterized as compounds having psychotropic activity that could be used, for example, for treating aggressive behavior, and ED50 values for a mouse model for fighting behavior were given in EP 0189612.
  • eltoprazine in the treatment of aggressive behaviour was tested in several clinical trials, for example in a trial of eltoprazine in the treatment of aggressive behavior in patients with epilepsy or Gilles de Ia Tourette's Syndrome (see Moriarty et al., Human Psychopharmacology: Clinical and Experimental, 9 (1994) 253-258), or in aggressive mentally handicapped patients (see de Koning et al., lnt Clin Psychopharmacol. 9 (1994) 187-94). While these clinical trials did not result in an approval of eltoprazine in these indications, eltoprazine did prove to be clinically safe (de Koning, loc. cit.).
  • GID graft-induced dyskinesia
  • Huntington's disease results from genetically programmed degeneration of brain neurons, in certain areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance (see information provided by National Institute of Neurological Disorders and Stroke).
  • Restless leg syndrome Restless leg syndrome (RLS) Restless legs syndrome (RLS) is a neurological disorder characterized by unpleasant sensations in the legs and an uncontrollable urge to move when at rest in an effort to relieve these feelings. RLS sensations are often described by people as burning, creeping, tugging, or like insects crawling inside the legs. Often called paresthesias (abnormal sensations) or dysesthesias (unpleasant abnormal sensations), the sensations range in severity from uncomfortable to irritating to painful (see information provided by National Institute of Neurological Disorders and Stroke).
  • the present invention relates to the use of eltoprazine and its salts, solvates and conjugates, which we have determined possesses a unique receptor profile. Consequently, the present invention relates to the use of eltoprazine for the treatment of a movement disorder taken from the list of: graft-induced dyskinesia (GID), Huntington's disease, and restless leg syndrome (RLS).
  • GID graft-induced dyskinesia
  • RLS restless leg syndrome
  • the present invention relates to a method of treating or preventing a movement disorder taken from the list of: graft-induced dyskinesia (GID), Huntington's disease, and restless leg syndrome (RLS) in a subject in need thereof, comprising administering an effective amount of eltoprazine or a pharmaceutically acceptable salt thereof.
  • a movement disorder taken from the list of: graft-induced dyskinesia (GID), Huntington's disease, and restless leg syndrome (RLS) in a subject in need thereof, comprising administering an effective amount of eltoprazine or a pharmaceutically acceptable salt thereof.
  • GID graft-induced dyskinesia
  • RLS restless leg syndrome
  • a further aspect of the invention relates to such a method comprising administering an effective amount of eltoprazine hydrochloride.
  • a further aspect of the invention relates to such a method wherein eltoprazine is administered in a range from about 5 mg to about 75 mg/day.
  • a further aspect of the invention relates to such a method wherein eltoprazine is administered in a range from about 5 mg to about 50 mg/day.
  • a further aspect of the invention relates to such a method wherein eltoprazine is administered in a range from about 5 mg to about 60 mg/day. [0016] A further aspect of the invention relates to such a method wherein eltoprazine is administered in a range from about 5 mg to about 40 mg/day.
  • a further aspect of the invention relates to such a method wherein eltoprazine is administered in a range from about 5 mg to about 20 mg/day.
  • a further aspect of the invention relates to such a method wherein eltoprazine is administered at about 20 mg/day.
  • a further aspect of the invention relates to such a method wherein eltoprazine is administered at about 40 mg/day.
  • a further aspect of the invention relates to such a method wherein eltoprazine is administered at about 60 mg/day.
  • a further aspect of the invention relates to such a method wherein eltoprazine is administered between about 10 and 15 mg/day.
  • a further aspect of the invention relates to such a method wherein eltoprazine or a pharmaceutically acceptable salt thereof is administered once a day, twice a day (b.i.d.), or three times a day.
  • a further aspect of the invention relates to such a method wherein eltoprazine is administered in an oral formulation.
  • a further aspect of the invention relates to a composition
  • eltoprazine or a pharmaceutically acceptable salt thereof e.g., eltoprazine hydrochloride
  • a movement disorder taken from the list of: graft-induced dyskinesia (GID), Huntington's disease, and restless leg syndrome (RLS).
  • GID graft-induced dyskinesia
  • RLS restless leg syndrome
  • a further aspect of the invention relates to the use of eltoprazine or a pharmaceutically acceptable salt thereof (e.g., eltoprazine hydrochloride) for the manufacture of a medicament for the treatment or prevention of a movement disorder taken from the list of: graft-induced dyskinesia (GID), Huntington's disease, and restless leg syndrome (RLS).
  • a movement disorder taken from the list of: graft-induced dyskinesia (GID), Huntington's disease, and restless leg syndrome (RLS).
  • a further aspect of the invention relates to the above-defined composition or use wherein eltoprazine or a pharmaceutically acceptable salt thereof (e.g., eltoprazine hydrochloride) is for administration in a range from about 5 mg to about 150 mg/day, or in a range from about 5 mg to about 100 mg/day, or in a range from about 5 mg to about 75 mg/day, in a range from about 5 mg to about 75 mg/day, or in a range from about 5 mg to about 60 mg/day, or in a range from about 5 mg to about 50 mg/day, or in a range from about 5 mg to about 40 mg/day, or in a range from about 5 mg to about 20 mg/day, or in a range from about 5 mg to about 15 mg/day, or wherein eltoprazine is for administration at about 10 mg/day, wherein eltoprazine is for administration at about 15 mg/day, is for administration at about 20 mg/day, or eltoprazine is for administration in a
  • a further aspect of the invention relates to the above-defined composition or use wherein eltoprazine or a pharmaceutically acceptable salt thereof (e.g., eltoprazine hydrochloride) is for administration once a day, twice a day (b.i.d.), or three times a day.
  • eltoprazine or a pharmaceutically acceptable salt thereof e.g., eltoprazine hydrochloride
  • a further aspect of the invention relates to the above-defined composition or use wherein eltoprazine or a pharmaceutically acceptable salt thereof (e.g., eltoprazine hydrochloride) is for administration in an oral formulation.
  • eltoprazine or a pharmaceutically acceptable salt thereof e.g., eltoprazine hydrochloride
  • a further aspect of the invention relates to a method comprising administering a therapeutically effective amount of eltoprazine or a pharmaceutically acceptable salt thereof in combination with at least one additional pharmaceutical agent which has been shown to be effective for the treatment of such movement disorder.
  • Figure 1 shows the potency of eltoprazine on different serotonin receptors at relevant plasma concentration ( ⁇ 0.5 ⁇ M).
  • Figure 2 shows the effect of eltoprazine on AIM scores in unilaterally 6-OHDA-lesioned rats.
  • Figure 3 shows the effect of eltoprazine on turning behavior induced by high dose of L-DOPA in unilaterally 6-OHDA-lesioned rats.
  • Figure 4 illustrates the effect of an acute treatment with eltoprazine 1 mg/kg, s.c. on the total distance traveled in the open field in the R6/2 mice.
  • the data are expressed as distances traveled in cm at week 8 for WT mice, Tg mice and Tg treated with eltoprazine. ** indicates a significant difference with p ⁇ 0.01 between Tg and Tg-treated animals (ANOVA).
  • Figure 5 illustrates the effect of acute treatment with eltoprazine 1 mg/kg, s.c. on the distance traveled in the center area of the open field in the R6/2 mice.
  • the data are expressed as distances traveled in cm at week 8 for WT mice, Tg mice and Tg treated with eltoprazine. * indicates a significant difference with p ⁇ 0.05 between Tg and Tg-treated animals (ANOVA).
  • Figure 6 illustrates the effects of acute administration of eltoprazine 1 mg/kg, s.c. on rotarod latency in the R6/2 mice.
  • the data are expressed as latency in seconds at week 9 for WT mice, Tg mice and Tg treated with eltoprazine. No significant differences between the Tg groups were found in rotarod latency.
  • Figure 7 illustrates the effects of acute administration of eltoprazine 1 mg/kg, s.c. on grip strength in the R6/2 mice.
  • the data are expressed as force (g) at week 10 for WT mice, Tg mice and Tg treated with eltoprazine. No significant differences between the Tg groups were found in grip strength.
  • Example 2 As shown in Example 2, the use of eltoprazine has shown positive effects in the treatment of levodopa-induced dyskinesias, and thus, it is expected that eltoprazine is beneficial in the treatment of GID as well.
  • the present invention relates to the use of eltoprazine and its salts, solvates and conjugates, which possesses a unique receptor profile targeting the 5-HT2a, 5-HT2c, 5-HT1a and 5-HT1b receptors at relevant plasma concentration. Furthermore, eltoprazine is devoid of significant affinity for the dopamine D2 receptor In theory, the unique efficacy could be achieved also through a cocktail of drugs mimicking these composite effects, however, such a cocktail of several molecules cannot successfully be developed in a clinical setting obeying regulatory requirements. [0044] As used herein, the term "subject" encompasses mammals including animals and humans.
  • eltoprazine is known in the art and may also be known as DU-28853 and 1-(2,3-dihydro-1 ,4-benzodioxin-5-yl)piperazine. As used herein, eltoprazine refers to the substance, as well as its pharmaceutically acceptable salts.
  • agonist refers to a substance that binds to a receptor and mimics the cellular effect of the native or endogenous ligand for the same receptor.
  • agonist includes the class of agents called full agonists, which bind and display full efficacy at the receptor, and partial agonists, which have only partial efficacy at the receptor. Partial agonists may also be seen as competitive antagonists, competing away the endogenous ligand when it is in excess or give a sub maximal response when inadequate amount of endogenous ligand is present.
  • activation refers to the state of a receptor when an agonist is bound to it.
  • treat is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical composition sufficient to result in a desired activity upon administration to a mammal in need thereof.
  • compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human).
  • pharmaceutically acceptable may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • salt is defined as a chemical containing different charged components.
  • the term salt also includes hydrates and solvates.
  • Contemplated in the instant description are pharmaceutically acceptable salts, which salts may include, but are not limited to, acid addition salts, such as those made with hydrochloric, sulphuric, nitric, phosphoric, acetic, maleic, fumaric, tartaric, citric, benzoic, methane sulphonic, naphthalene sulphonic, p-toluene sulphonic acid. All of these salts (or other similar salts) may be prepared by conventional means. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • Eltoprazine may be used according to the invention in the form of any of pharmaceutically acceptable salts, solvates and conjugates. Any references to eltoprazine in this description should be understood as also referring to such salts, solvates and conjugates.
  • carrier applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound (e.g., eltoprazine) is administered.
  • active compound e.g., eltoprazine
  • Such pharmaceutical carriers may be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by A. R. Gennaro, 20 th Edition.
  • the term “about” or “approximately” usually means within 20%, alternatively within 10%, including within 5% of a given value or range. Alternatively, especially in biological systems, the term “about” means within about a log (i.e., an order of magnitude), including within a factor of two of a given value.
  • compositions comprising a therapeutically effective amount of eltoprazine.
  • the compositions of the invention may further comprise a carrier or excipient (all pharmaceutically acceptable).
  • the compositions may be formulated e.g. for once-a-day administration, twice-a- day administration, or three times a day administration.
  • the active ingredient e.g., eltoprazine
  • the composition of the present invention may be used for the treatment of at least one of the mentioned disorders, wherein the treatment is adapted to or appropriately prepared for a specific administration as disclosed herein (e.g., to once-a- day, twice-a-day, or three times a day administration).
  • the package leaflet and/or the patient information contains corresponding information.
  • a therapeutically effective amount of eltoprazine is administered twice per day.
  • eltoprazine is administered once in the morning, and once in the middle of the day, particularly at about lunchtime, wherein the lunchtime treatment is between about 6 and 10, particularly between about 7 and 9 hours before the patient wishes to go to bed.
  • Such an administration should allow for the eltoprazine plasma level to ebb away during evening and at nighttime, reducing the risk of an impaired REM-(rap/d eye movement-activity.
  • the treatment is the treatment of restless leg syndrome (RLS).
  • RLS restless leg syndrome
  • the first dosage of eltoprazine consist of about 55 to 65% of the total daily dosage amount, and the second dose of eltoprazine comprising the remaining total daily dosage amount.
  • the active ingredient (e.g., eltoprazine) or the composition of the present invention may be used for the manufacture of a medicament for the treatment of at least one of the mentioned disorders, wherein the medicament is adapted to or appropriately prepared for a specific administration as disclosed herein (e.g., to once-a-day, twice-a-day, or three times a day administration).
  • the package leaflet and/or the patient information contains corresponding information.
  • the dosage form of eltoprazine, or an eltoprazine salt may be a solid, semisolid, or liquid formulation according to the following.
  • Eltoprazine may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers.
  • eltoprazine may be formulated as a flavored liquid (e.g., peppermint flavor).
  • Eltoprazine may be administered orally in the form of a capsule, a tablet, granules, pellets or the like, or as a semi-solid, or liquid formulation (see Remington's Pharmaceutical Sciences, 20 th Edition, by A.R. Gennaro).
  • eltoprazine may be combined with non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as aca).
  • binding agents e.g., pregelatinized mai
  • the tablets may be coated with a concentrated sugar solution which may contain e.g., gum arabic, gelatine, talcum, titanium dioxide, and the like.
  • a concentrated sugar solution which may contain e.g., gum arabic, gelatine, talcum, titanium dioxide, and the like.
  • the tablets may be coated with a polymer that dissolves in a readily volatile organic solvent or mixture of organic solvents.
  • eltoprazine is formulated in immediate-release (IR) or modified-release (MR) tablets.
  • Immediate release solid dosage forms permit the release of most or all of the active ingredient over a short period of time, such as 60 minutes or less, and make rapid absorption of the drug possible.
  • Modified release solid oral dosage forms permit the sustained release of the active ingredient over an extended period of time in an effort to maintain therapeutically effective plasma levels over similarly extended time intervals and/or to modify other pharmacokinetic properties of the active ingredient.
  • eltoprazine may be formulated in a modified release dosage form (including modified release tablets) to provide a dose of eltoprazine.
  • eltoprazine may be admixed with e.g., a vegetable oil or polyethyleneglycol.
  • Hard gelatin capsules may contain granules of the active substances using either the above-mentioned excipients for tablets e.g., lactose, saccharose, sorbitol, mannitol, starches (e.g., potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.
  • liquids or semisolids of the drug may be filled into hard gelatine capsules.
  • Eltoprazine may also be introduced in microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA) (see, e.g., U.S. Patents No. 5,814,344; 5,100,669 and 4,849,222; PCT Publications No. WO 95/11010 and WO 93/07861).
  • PGLA polyglycolic acid/lactic acid
  • Biocompatible polymers may be used in achieving controlled release of a drug, include for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, poly(epsilon-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • eltoprazine in a semi-solid or liquid form may also be used.
  • Eltoprazine may constitute between 0.1 and 99% by weight of the formulation, more specifically between 0.5 and 20% by weight for formulations intended for injection and between 0.2 and 50% by weight for formulations suitable for oral administration.
  • modified release dosage forms provide a means for improving patient compliance and for ensuring effective and safe therapy by reducing the incidence of adverse drug reactions. Compared to immediate release dosage forms, modified release dosage forms may be used to prolong pharmacologic action after administration, and to reduce variability in the plasma concentration of a drug throughout the dosage interval, thereby eliminating or reducing sharp peaks.
  • a modified release dosage form may comprise a core either coated with or containing a drug.
  • the core is then coated with a release-modifying polymer within which the drug is dispersed.
  • the release-modifying polymer disintegrates gradually, releasing the drug over time.
  • the outer-most layer of the composition effectively slows down and thereby regulates the diffusion of the drug across the coating layer when the composition is exposed to an aqueous environment, i.e. the gastrointestinal tract.
  • the net rate of diffusion of the drug is mainly dependent on the ability of the gastric fluid to penetrate the coating layer or matrix and on the solubility of the drug itself.
  • eltoprazine is formulated in an oral, liquid formulation.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
  • eltoprazine may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p- hydroxybenzoates or sorbic acid), and the like.
  • inert carriers e.g., ethanol, glycerol, water
  • suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters, ethyl alcohol
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
  • solutions may contain from about 0.2% to about 20% by weight of eltoprazine, with the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol.
  • such liquid formulations may contain coloring agents, flavoring agents, saccharine and carboxymethyl-cellulose as a thickening agent or other excipients.
  • a therapeutically effective amount of eltoprazine is administered in an oral solution containing a preservative, a sweetener, a solubilizer, and a solvent.
  • the oral solution may include one or more buffers, flavorings, or additional excipients.
  • a peppermint or other flavoring is added to the eltoprazine oral liquid formulation.
  • eltoprazine may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • Solutions for parenteral applications by injection may be prepared in an aqueous solution of the compound or of a water-soluble pharmaceutically acceptable salt of the active substances, for example in a concentration of from about 0.5% to about 10% by weight.
  • These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
  • the formulations of the invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers containing eltoprazine and, optionally, more of the ingredients of the formulation.
  • eltoprazine is provided as an oral solution for administration with the use of a 2-teaspoon capacity syringe (dosage KORC®).
  • DORC® 2-teaspoon capacity syringe
  • Each oral syringe has hatch marks for measurement, with lines on the right side of the syringe (tip down) representing tsp units, and those on the left representing ml units.
  • the optimal therapeutically effective amount may be determined experimentally, taking into consideration the exact mode of administration, form in which the drug is administered, the indication toward which the administration is directed, the subject involved (e.g., body weight, health, age, sex, etc.), and the preference and experience of the physician or veterinarian in charge.
  • Dosage units for rectal application may be solutions or suspensions or may be prepared in the form of suppositories or retention enemas comprising eltoprazine in a mixture with a neutral fatty base, or gelatin rectal capsules comprising the active substances in admixture with vegetable oil or paraffin oil.
  • Toxicity and therapeutic efficacy of the compositions of the invention may be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD 5 o/ED 5O .
  • Compositions that exhibit large therapeutic indices are preferred.
  • Suitable daily doses of the active ingredient of the invention (eltoprazine) in therapeutic treatment of humans are within the range from about 5 mg to about 150 mg per day, such as from about 5 mg to about 120 mg, from about 5 mg to about 100 mg, or from about 5 mg to about 75 mg, or from about 5 mg to about 60 mg, or from about 5 mg to about 50 mg, or from about 10 mg to about 20 mg, or from about 10 mg to about 15 mg, such as 10mg or 15 mg or 20 mg or 30 mg or 40 mg or 60mg or 80mg, per day.
  • the daily dose may be body weight-adjusted such as 40 mg/day up to 80 kg body weight or 60 mg/day for patients with a body weight of > 80 kg.
  • the amounts of active ingredient per day could also be higher due to reduced bioavailability, e.g. up to 200 mg/day.
  • eltoprazine may be administered as an oral, liquid dosage form, at reduced amounts, for example from about 1 mg/day, up to about 5 mg/day.
  • the daily dosage of eltoprazine is between about 10 and 20 mg/day.
  • the daily doses indicated herein may be administered, for example, as one or two dosing units once, twice or three times per day. Suitable doses per dosage unit may therefore be the daily dose divided (for example, equally) between the number of dosage units administered per day, and will thus typically be about equal to the daily dose or one half, one third, one quarter or one sixth thereof. Dosages per dosage unit may thus be calculated from each daily dosage indicated herein.
  • a daily dose of 5 mg for example may be seen as providing a dose per dosage unit of, for example, about 5 mg, 2.5 mg, 1.67 mg, 1.25 mg and 0.83 mg, depending upon the dosing regimen chosen.
  • a dosage of 50 mg per day corresponds to dosages per dosing unit of, for example, about 50 mg, 25 mg, 16.7 mg, 12.5 mg, and 8.33 mg for corresponding dosing regimens.
  • an unequal split of the first and the second dosage is envisaged.
  • the first dosage comprises about 55 to 65% of the total daily dosage.
  • a daily dosage of 10 mg is split into a first dosage of 6 mg and a second dosage of 4 mg.
  • the dosage might be split also unequally, wherein the second and further dosages are reduced in comparison to the dosage before.
  • the first dosage could be about one half of the total daily dosage, i.e. between about 40% to 60%
  • the second dosage could be about one third of the total daily dosage, i.e. between about 20% to 40%
  • the third dosage could be about one sixth of the total daily dosage, i.e. between about 5% to 20%.
  • a daily dosage of 10 mg could be split into a first dosage of 6 mg, a second dosage of 3 mg and a third dosage of 1 mg.
  • Treatment duration may be short-term, e.g., several weeks (for example 8-14 weeks), or long-term until the attending physician deems further administration no longer is necessary.
  • Eltoprazine may be administered as a single agent, or in combination with another agent.
  • compositions each comprising an active agent (e.g. eltoprazine, and another pharmaceutical composition comprising another agent prescribed for the treatment of such motor disorders, to be administered conjointly.
  • active agent e.g. eltoprazine
  • another pharmaceutical composition comprising another agent prescribed for the treatment of such motor disorders, to be administered conjointly.
  • the term “conjoint administration” is used to refer to administration of eltoprazine, and a second active agent simultaneously in different compositions, or sequentially.
  • sequential administration to be considered “conjoint”, however, eltoprazine, and the second active agent must be administered separated by a time interval, which still permits the resultant beneficial effect for treating L- DOPA-induced dyskinesias in a mammal.
  • EXAMPLE 1 Neurochemical profile of eltoprazine
  • Eltoprazine was tested for activity on the human serotonin 5-HT1a and 5-HT1b receptors using a GTP ⁇ S assay.
  • Recombinant membranes obtained from CHO-K1 cells expressing either the 5-HT1a or 5-HT1b receptors were mixed with GDP (volume:volume) and incubated for at least 15 min on ice.
  • GTP ⁇ [35S] was mixed with the beads (volume:volume) just before starting the reaction.
  • 5-HT2a, 5-HT2b and 5-HT2c non-edited receptor
  • Aequorin cell lines expressing the 5-HT2a, 5-HT2b and 5-HT2c non- edited (ne) recombinant receptors were used to evaluate the functional activity of eltoprazine.
  • Aequorin cells grown 18 h prior to the test in media without antibiotics were detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in "assay buffer" (DMEM/HAM's F12 with HEPES + 0.1% BSA protease free). Cells were incubated at room temperature for at least 4h with Coelenterazine h (Molecular Probes).
  • the reference agonist used were 5-HT and ⁇ -methyl-5- HT.
  • 50 ⁇ l of cell suspension were injected on 50 ⁇ l of test compound or reference agonist plated in a 96-well plate. The resulting emission of light was recorded using the Hamamatsu Functional
  • Figure 1 illustrates the potency of eltoprazine on different serotoninergic receptor activated at relevant plasma concentration.
  • EXAMPLE 2 Effect of eltoprazine on L-DOPA Induced Dyskinesia in the 6-hvdroxydopamine ( ⁇ -OHDA)-lesioned rat model of Parkinson's disease
  • 6-OHDA-HCI 6-hydroxydopamine
  • Injections are performed at the rate of 1 ⁇ l/min (allowing an additional 3 min before retracting the needle) using a 10 ⁇ l Hamilton microsyringe with a 26-gauge steel cannula.
  • all rats are tested for amphetamine-induced rotation 2 weeks after the 6-OHDA injections.
  • the animals' turning behaviour is recorded in an automated rotameter (TSE Rotameter System, TSE- Systems GmbH, Bad Homburg, Germany) over a 90 min period after the intraperitoneal (i.p.) injection of 2.5 mg/kg dexamphetamine sulphate dissolved in saline. Only the rats showing rotational scores > 5 net full turns/min in the direction ipsilateral to the lesion are selected for the study.
  • rats are treated for 21 days with a single daily i.p. injection of 6 mg/kg of L-DOPA mixed with 15 mg/kg of the peripheral DOPA-decarboxylase inhibitor benserazide hydrochloride or with saline (vehicle controls).
  • L-DOPA and benserazide are dissolved in a physiological saline solution.
  • Chronic treatment with this dose of L-DOPA has been shown to induce gradual development of dyskinetic-like movements in 6-OHDA-lesioned rats. After approx.
  • rats are injected 30 min before the evaluation of abnormal involuntary movement (AIM)s with different doses of eltoprazine hydrochloride (0.08, 0.3, 1.25 and 5 mg/kg, s.c), followed by L-DOPA (L- DOPA 6 mg/kg, and benserazide 15 mg/kg), i.p., 10 min before the beginning of the test.
  • AIM abnormal involuntary movement
  • Repetitive movements affecting the side of the body contralateral to the lesion that could not be ascribed to any normal behavioural pattern are classified into four different subtypes: locomotive AIMs, i.e., increased locomotion with contralateral side bias; axial dystonia, i.e., contralateral twisted posturing of the neck and upper body; orolingual AIMs, i.e., stereotyped jaw movements and contralateral tongue protrusion; and forelimb dyskinesia, i.e., repetitive jerks of the contralateral forelimb, sometimes combined with grabbing movements of the paw.
  • locomotive AIMs i.e., increased locomotion with contralateral side bias
  • axial dystonia i.e., contralateral twisted posturing of the neck and upper body
  • orolingual AIMs i.e., stereotyped jaw movements and contralateral tongue protrusion
  • forelimb dyskinesia i.e., repetitive jerks of the contralateral forelimb, sometimes combined with
  • the axial, orolingual and forelimb (AOL) AIMs are presented together as a mean (mean AIM score) per time point.
  • L-DOPA (6.25 mg/kg + Benserazide 15 mg/kg) is injected alone or in combination with eltoprazine at 0.08, 0.3, 1.25 and 5 mg/kg.
  • ANOVA and two-way ANOVA are used to evaluate the significance of the results. Post hoc Tukey test is performed where appropriate.
  • Figure 2 illustrates the effect of increasing doses of eltoprazine on AIM scores in 6-OHDA-lesioned rats.
  • the data are expressed as % of AIM scores compared to L-DOPA - vehicle-treated animals. * indicates a significant difference with p ⁇ 0.05 between L-DOPA - vehicle-treated animals (ANOVA).
  • Figure 3 illustrates the effect of eltoprazine on the turning behaviour induced by high dose of L-DOPA in 6-OHDA-lesioned rats. * indicates a significant difference with p ⁇ 0.05 versus vehicle-treated animals, # indicates a significant different with p ⁇ 0.05 versus eltoprazine-treated animals (2-way ANOVA followed by Tukey's Post hoc test).
  • EXAMPLE 3 Eltoprazine in an in vivo model for Huntinqton's Disease
  • mice (B6CBA- Tg(HDexon1)62Gpb/3J) and 10 (6 females and 4 males) wild-type littermates were used for the study.
  • Animals were housed at a standard temperature (22 ⁇ 1°C) and in a light-controlled environment (lights on from 7 am to 8 pm) with ad libitum access to food and water. All animal experiments were carried out according to the National Institute of Health (NIH) guidelines for the care and use of laboratory animals. Body weight was measured once-a-week starting at the age of 4 weeks and the mice were terminated at 12 weeks of age.
  • NASH National Institute of Health
  • mice received on test day 1 vehicle and test day 3 eltoprazine, and 10 mice received on test day 1 eltoprazine and test day 3 vehicle).
  • Eltoprazine hydrochloride was dissolved in sterile water. Administration of eltoprazine or vehicle (sterile water) were done s.c. (1 mg/kg) once 45 min prior to start of the behavioural assay. WT mice received vehicle only whereas cross-over study design was applied to the Tg group. 10 randomly selected mice received on test day 1 vehicle and test day 3 eltoprazine, and the remaining 10 mice received on test day 1 eltoprazine and test day 3 vehicle.
  • Rotarod was performed at age week 9 (Hockly et al., 2003). Each session started with a training trial of 5 min at 4 RPM on the rotarod apparatus (AccuScan Instruments, Columbus, OH). After training trial the vehicle or eltoprazine was administered and 45 min later, the animals were tested for 3 consecutive accelerating trials of 6 min with the speed changing from 0 to 40 RPM over 360 seconds and an inter-trial interval at least 30 min. The latency to fall from the rod was recorded. Mice remaining on the rod for more than 360 s were removed and their time scored as 360 sec. 10 randomly selected mice received on test day 1 vehicle and test day 3 eltoprazine, and the remaining 10 mice received on test day 1 eltoprazine and test day 3 vehicle. Baseline behaviour was done once-a-week at age week 4.
  • Grip strength measurement was performed at age week 10. Mice were taken to the experimental room and, one at a time, were placed on the grip-strength apparatus (San Diego Instruments, San Diego, USA) in such a way that the animal grabs a small mesh grip with its forepaws. The entire apparatus was placed on a table top for testing. Animals were lowered to the platform and then slowly pulled away from the handle by the tail until the animal released the handle. The equipment automatically measures the strength of the animal's grip in grams. Five scores were recorded per animal in consecutive sequence. Mice were returned to their home cage after testing. 10 randomly selected mice received on test day 1 vehicle and test day 3 eltoprazine, and the remaining 10 mice received on test day 1 eltoprazine and test day 3 vehicle. Baseline behaviour was done once-a- week at age week 4.

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Abstract

La présente invention porte sur le traitement d'un individu atteint d'un certain trouble du mouvement, le présent traitement comprenant l'administration à l'individu d'une quantité efficace d'eltoprazine ou d'un sel pharmaceutiquement acceptable de celle-ci.
PCT/EP2010/003963 2009-06-30 2010-06-30 Eltoprazine pour le traitement de certains troubles du mouvement WO2011000562A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2792359A1 (fr) * 2013-04-19 2014-10-22 Merz Pharma GmbH & Co. KGaA Traitement de la dyskinésie induite par L-DOPA avec OPC-14523 ou OPC-34712

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2792359A1 (fr) * 2013-04-19 2014-10-22 Merz Pharma GmbH & Co. KGaA Traitement de la dyskinésie induite par L-DOPA avec OPC-14523 ou OPC-34712

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