WO2007144422A2 - Préparations combinées contenant du bifeprunox et de la l-dopa - Google Patents

Préparations combinées contenant du bifeprunox et de la l-dopa Download PDF

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Publication number
WO2007144422A2
WO2007144422A2 PCT/EP2007/055956 EP2007055956W WO2007144422A2 WO 2007144422 A2 WO2007144422 A2 WO 2007144422A2 EP 2007055956 W EP2007055956 W EP 2007055956W WO 2007144422 A2 WO2007144422 A2 WO 2007144422A2
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WIPO (PCT)
Prior art keywords
dopa
bifeprunox
administration
disease
treatment
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PCT/EP2007/055956
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English (en)
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WO2007144422A3 (fr
Inventor
Andrew C. Mccreary
Gustaaf J.M. Van Scharrenburg
Martinus Th. M. Tulp
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Solvay Pharmaceuticals B.V.
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Priority to JP2009514810A priority Critical patent/JP2009539942A/ja
Priority to CA002654557A priority patent/CA2654557A1/fr
Priority to EA200970022A priority patent/EA014576B1/ru
Priority to BRPI0713691-9A priority patent/BRPI0713691A2/pt
Priority to EP07730194A priority patent/EP2037964A2/fr
Priority to MX2008016226A priority patent/MX2008016226A/es
Priority to AU2007259256A priority patent/AU2007259256A1/en
Publication of WO2007144422A2 publication Critical patent/WO2007144422A2/fr
Publication of WO2007144422A3 publication Critical patent/WO2007144422A3/fr
Priority to IL195493A priority patent/IL195493A0/en
Priority to NO20090165A priority patent/NO20090165L/no

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention concerns the use of a combination preparation of bifeprunox or its N-oxide, or pharmacologically acceptable salts of those compounds:
  • Constant tremors in hands and legs, body movements that gradually become stiffer, slower and weaker, and mask-like facial expressions, are symptoms that have been observed throughout the history of centuries.
  • James Parkinson described this cluster of symptoms as
  • Parkinson's disease involves destruction of nerve cells in the substantia nigra, the part of the brain involved with muscle movements. Loss of around 80% of striatal dopamine in Parkinson's disease results in cardinal symptoms of akinesia, rigidity and bradykinesia (Hornykiewicz, 1966). Patients have problems initiating movement and exhibit postural instability and loss of coordination.
  • L-DOPA the levorotatory enantiomer of 3,4-dihydroxyphenylalanine
  • Carbidopa inhibits decarboxylation of peripheral levodopa but cannot itself cross the blood brain barrier, and has no effect on the metabolism of levodopa in the brain.
  • the combination of carbidopa and levodopa is considered to be the most effective treatment for symptoms of Parkinson's disease. Nevertheless, certain limitations become apparent within two to five years of initiating therapy. As the disease progresses, the benefit from each dose becomes shorter ("the wearing off effect") and some patients fluctuate unpredictably between mobility and immobility (“the on-off effect”). "On" periods are usually associated with high plasma levodopa concentrations and often include abnormal involuntary movements, i.e., dyskinesias.
  • 5-HT 1A receptor agonists may ameliorate the induction of dyskinesia since the 5-HT 1A receptor agonist tandospirone reduced dyskinesia in L-DOPA treated Parkinson's disease patients
  • 5-HT 1A receptor agonist could be beneficial to the therapeutic effects of a partial D 2 /3 receptor agonist (Johnston, 2003).
  • L-DOPA/carbidopa e.g. Sinemet ®
  • L-DOPA/benserazide e.g. Madopar ®
  • L-DOPA/carbidopa/entacapone e.g. Stalevo ® , (Jost, 2005)
  • catecholamine-O-methyltransferase (COMT) inhibitors such as tolcapone and entacapone have been proposed as adjunctive therapy to L-DOPA.
  • MAO-B monoamine oxidase-B
  • Characteristic for combination preparations is that they exist in many different dose combinations, because during the course of the disease usually higher doses of L-DOPA are necessary to keep the symptoms under control.
  • Combination preparations in the form of tablets containing fixed amounts of drugs are easy to use, but simultaneously also offer limited flexibility.
  • An illustration of the fact that fixed combinations are not universally useful is e.g. the use of the selective MAO-B inhibitor selegiline in the treatment of Parkinson's disease.
  • selegiline may be given as monotherapy: the compound will slow down the metabolism of endogenous dopamine enough to keep the symptoms within tolerable limits.
  • the use of L-DOPA can become necessary.
  • L-DOPA When the efficacy of L-DOPA starts to wear, usually the first solution to that problem is the use of a decarboxylase inhibitor like carbidopa (see above), and when also that gets insufficient, co-therapy with selegiline will restore L-DOPAs efficacy by reducing the breakdown of the dopamine generated from the L-DOPA.
  • a decarboxylase inhibitor like carbidopa (see above)
  • co-therapy with selegiline will restore L-DOPAs efficacy by reducing the breakdown of the dopamine generated from the L-DOPA.
  • L-DOPA and selegiline are administered in separate preparations which may be given simultaneously or sequentially.
  • RLS is indicated when four diagnostic criteria are met: (1 ) a sensation of an urge to move the limbs (usually the legs); (2) motor restlessness to reduce sensations; (3) when at rest, symptoms return or worsen; and (4) marked circadian variation in occurrence or severity of RLS symptoms; that is, symptoms worsen in the evening and at night (Allen, 2001).
  • RLS Current treatments for RLS are varied and plagued with undesirable side effects.
  • Therapies have included the administration of dopamine agonists, other dopaminergic agents, benzodiazepines, opiates and anti-convulsants.
  • a secondary condition such as pregnancy, end-stage renal disease, erythropoietin treatment, or iron deficiency
  • removing the condition such as giving birth or treating with traditional iron supplementation, can reduce or eliminate symptoms in at least some cases (Allen, 2001).
  • RLS resulting from non-secondary conditions (“idiopathic" RLS) presents a greater treatment challenge.
  • Dopaminergic agents such as levodopa generally provide effective initial treatment, but with continued use, tolerance and symptom augmentation occur in about 80% of RLS patients (Allen, 1996); this complication is also common for dopamine agonists (Earley, 1996).
  • the other alternatives, benzodiazepines, opiates and anti-convulsants are not as uniformly effective as the dopaminergic agents (Chesson, 1999; Hening, 1999).
  • 15-20% of patients find that all medications are inadequate because of adverse effects and limited treatment benefit bifeprunox N-oxide
  • the goal of the present invention was to develop a treatment as effective as L-DOPA, but without its side effects: In particular without its characteristic "on -off effect", causing dyskinesias during "on"-periods, and bradykinetic episodes during "off” -periods.
  • the subject matter of the invention are combination preparations of bifeprunox or its N-oxide, or pharmacologically acceptable salts, hydrates and solvates thereof, and L-DOPA and, optionally, a decarboxylase inhibitor and/or, optionally, a COMT-inhibitor, and/or, optionally, a MAO-B inhibitor, for simultaneous, separate or sequential use in therapy of disorders requiring recovery of dopaminergic function, in particular Parkinson's disease and 'Restless Leg syndrome'.
  • the invention relates to the use of bifeprunox or its N-oxide, a true 'prodrug', in cases in which a L-DOPA induces dyskinesias, or can be anticipated to induce dyskinesias.
  • the specific pharmacological activities of the compound viz., partial agonism on dopamine-D 2 and dopamine-D 3 receptors, as well as full agonism on serotonin 5-HT 1A receptors, result in a blockade of the dyskinesias without reducing the therapeutic effect of L-DOPA.
  • the present invention relates to pharmaceutical formulations, comprising: (i) bifeprunox, its N-oxide, or pharmacologically acceptable salts, hydrates and solvates thereof, and:
  • kits of parts comprising: (i) a vessel containing bifeprunox, its N-oxide, or pharmacologically acceptable salts, hydrates, and solvates thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, and:
  • a vessel containing L-DOPA optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, and: (iii) instructions for the sequential, separate or simultaneous administration of bifeprunox and the L-DOPA, to a patient in need thereof.
  • a method of making a kit of parts as defined herein comprises bringing a component (i), as defined above, into association with a component (ii), as defined above, thus rendering the two components suitable for administration in conjunction with each other.
  • Bringing the two components into association with each other includes that components (i) and (ii) may be:
  • Yet another aspect of the invention relates to methods for treatment of a patient suffering from, or susceptible to, a condition in which recovery of dopaminergic function is required or desired, which method comprises administering to the patient a therapeutically effective total amount of:
  • Still another aspect of the invention relates to the use of pharmaceutical formulations, comprising:
  • L-DOPA in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, in the manufacture of a medicament for the treatment of a condition in which recovery of dopaminergic function is required or desired.
  • Examples of decarboxylase inbitors are: carbidopa and benserazide.
  • Examples of catechol- amine-O-methyl transferase (COMT) inhibitors are: entacapone, nitecapone and tolcapone, and monoamine oxidase-B (MAO-B) inhibitors include: deprenyl, (-)-deprenyl (selegiline), desmethyldeprenyl, N-propargyl-1-(R)-aminoindan (rasagaline), phenelzine (nardil), tranylcypromine (parnate), CGP3466, furazolidone, isocarboxazid, pargyline, methyclothiazide and procarbazine
  • composition encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts.
  • this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the term 'combination preparation' comprises both true combinations, meaning bifeprunox and other medicaments physically combined in one preparation such as a tablet or injection fluid, as well as 'kit-of-parts', comprising bifeprunox and L-DOPA in separate dosage forms, together with instructions for use, optionally with further means for facilitating compliance with the administration of the component compounds, e.g. label or drawings.
  • the pharmacotherapy by definition is simultaneous.
  • the contents of 'kit-of-parts' can be administered either simultaneously or at different time intervals. Therapy being either concomitant or sequential will be dependant on the characteristics of the other medicaments used, characteristics like onset and duration of action, plasma levels, clearance, etc., as well as on the disease, its stage, and characteristics of the individual patient.
  • the dose of the composition to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician.
  • the dosage will preferably be in the range of from 0.01 mg/kg to 10 mg/kg.
  • the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
  • oral and parenteral dosages will be in the range of 0.1 to 1 ,000 mg per day of total active ingredients.
  • terapéuticaally effective amount refers to an amount of a therapeutic agent to treat a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative response in a tissue system, animal or human. The effect may include, for example, treating the conditions listed herein.
  • the precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the therapeutics, or combination of therapeutics, selected for administration. Thus, it is not useful to specify an exact effective amount in advance.
  • pharmaceutically acceptable salt refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well- known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid or an organic acid.
  • administering in conjunction with includes that respective formulations comprising bifeprunox and L-DOPA are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition, which condition may be acute or chronic.
  • the term includes that the two formulations are administered (optionally repeatedly) sufficiently closely in time for there to be a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either of the two formulations are administered (optionally repeatedly) alone, in the absence of the other formulation, over the same course of treatment.
  • the term "in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration with the other component.
  • the terms "administered simultaneously” and “administered at the same time as” include that individual doses of bifeprunox and L-DOPA are administered within 48 hours, e.g. 24 hours, 18 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour or 30 minutes of each other.
  • treatment refers to any treatment of a mammalian, preferably human condition or disease, and includes: (1 ) inhibiting the disease or condition, i.e., arresting its development, (2) relieving the disease or condition, i.e., causing the condition to regress, or (3) stopping the symptoms of the disease.
  • medical therapy intendeds to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • Drug treatment Bifeprunox mesylate was suspended in 10% sucrose solution and administered orally by gavage in a volume of 2.0 ml/kg.
  • L-DOPA L-3,4-Dihydroxyphenylalanine (L-dopa) methylester (Sigma Chemical Co, UK) was dissolved in 10% sucrose solution and administered orally by gavage in a volume of 2.0 ml/kg.
  • Carbidopa (Merck, Sharp and Dohme, UK) was administered orally as a suspension in 10% sucrose solution in a volume of 2.0 ml/kg.
  • Domperidone (2.0 mg/kg po, Sigma UK) was dissolved in 10% sucrose and administered 60 min prior to bifeprunox in a volume of 2.0 ml/kg.
  • Hyperactivity was defined as 3 times normal activity in naive marmosets. 'On' time was the period of time in minutes that activity was above the 'On' Threshold. Animals were treated with bifeprunox, vehicle and/or L-DOPA. Following drug treatment, animals were assessed for locomotor activity and disability as described below for up to 6 h following drug administration. The animals used in the study were in the automated activity cages for no longer than 8 h on any study day, and were allowed at least 3 days recovery period between drug treatments to ensure appropriate animal welfare consideration. The locomotor activity, motor disability and presence of dyskinesia were assessed as follows:
  • Locomotor Activity In all studies the animals were acclimatised to behavioural study cages for 1 hour prior to bifeprunox treatment. Animals were then treated with appropriate drugs. Following treatment, animals were assessed for antiparkinsonian activity for up to 6 h using automated activity cages and by the rating of disability by an observer blinded to the treatment. Locomotor 'On-time' was defined as the period of time the animals showed activity above 3 x baseline locomotor activity or a locomotor activity of 100 which ever was greater.
  • Disability and dyskinesia scores were assessed before, and during the last 10 minutes in every 30 min period after bifeprunox administration for up to 6 hours following drug treatment. The following disability rating scales were used:
  • the disability of animals was scored as follows; alertness (normal 0, sleepy 2); reaction (normal 0, reduced 1 , slow 2, absent 3); checking movements (present 0, reduced 1 , absent 2); attention and eye movements (normal 0, abnormal 1 ); posture (normal 0, abnormal trunk +1 , abnormal limbs +1 , abnormal tail +1 , or grossly abnormal 4); balance/coordination (normal 0, impaired 1 , unstable 2, spontaneous falls 3); vocalisation (normal 0, reduced 1 , absent 2); motility (normal 0, bradykinesia/hyperkinesia 1 , akinesia/hyperkinesia 2). Sedation was noted if present. Disability 'On-time' was defined as the period of time the animals showed a disability score of 6 or less ('On threshold').
  • Data and Statistical Analysis Data are presented as median locomotor activity (counts/30 min) or disability score (score over 10 min/30 min) over the 7 hour period of the experiment, or as total locomotor activity (counts/420 min) or disability (total score over 420min). Data were analysed by Kruskall Wallis ANOVA and post-hoc Man-Whitney test where appropriate. Analyses were corrected for multiple comparisons using the formula:
  • EXAMPLE 2 Effects of bifeprunox on L-DOPA induced reversal of motor disabilities
  • Locomotor Activity L-DOPA (7.5 mg/kg po) plus carbidopa (12.5 mg/kg po 30 min prior to L- DOPA) increased locomotor activity compared to vehicle administration (Fig 1 , 2, 3 and 4) immediately after administration. Peak activity (median 1627, range 832-2289 counts per 30 min) was reached between 60 and 180 min after administration of L-DOPA. The median duration of activity (On-Time) was 180 min/420 min (Fig 4). Total locomotor activity and locomotor 'on-time' was greater than vehicle-treated animals (p ⁇ 0.05, Mann Whitney).
  • Bifeprunox (4 mg/kg po) increased locomotor activity compared to vehicle administration (Fig 1 and 3) immediately after administration. Peak activity (median 685, range 512-1967 counts per 30 min) was reached between 60 and 180 min after administration. The median duration of activity (On-Time) was 240min/420 min (Fig 4). Total locomotor activity and locomotor 'On- Time' were greater than in vehicle-treated animals (p ⁇ 0.05, Mann Whitney).
  • Bifeprunox (8 mg/kg po) increased locomotor activity compared to vehicle administration (Fig 2 and 3) immediately after administration. Peak activity (median 1 110, range 669-2058 counts per 30 min) was reached between 60 and 300 min after administration. The median duration of activity (On-Time) was 345min/420 min was greater than vehicle treatment (Fig 4). Total locomotor activity was greater than vehicle-treated animals (p ⁇ 0.05, Mann Whitney). Pretreatment with bifeprunox (4 mg/kg po), 90 min prior to L-DOPA (7.5 mg/kg po) plus carbidopa (12.5 mg/kg po, 30 min prior to L-DOPA), increased locomotor activity compared to baseline (Fig 2 and 3) immediately after administration.
  • Peak activity (median 1581 , range 556- 2232 counts per 30 min) was reached between 60 to 390 min after administration.
  • the median duration of activity (On-Time, 390min/420min, Fig 4) was slightly greater than that seen after L- DOPA alone and bifeprunox.
  • Locomotor activity tended to increase compared to L-DOPA alone and bifeprunox (4 mg/kg po) alone ( Figure 1 , 2, 3 and 4).
  • L-DOPA (7.5 mg/kg po) plus carbidopa (12.5 mg/kg po 30 min prior to L-DOPA) decreased disability scores compared to vehicle administration (Fig 5,6,7 and 8) immediately after administration (p ⁇ 0.05 compared to vehicle treated control, Mann Whitney). Peak activity (median score, 3; score range 2-4) was reached between 30 and 300 (median 75) minutes after administration of L-DOPA.
  • the disability 'On-Time' for L-DOPA alone was 120min/420min.
  • Bifeprunox (4 mg/kg po) decreased disability scores compared to vehicle administration (Fig 5 and 7) immediately (30-60min) after administration (p ⁇ 0.05 compared to vehicle-treated control,
  • Bifeprunox (8 mg/kg po) decreased disability scores compared to vehicle treatment immediately after administration (Fig 6 and 7) (p ⁇ 0.05 compared to vehicle treated control, Mann Whitney). Total decrease in disability was lower than vehicle-treated animals ( Figure 7). Peak scores (median 4, range 2-5) were reached between 30 and 150 min after administration. Duration of activity (On-Time) was 225min/420min was greater than vehicle treatment (Fig 8).
  • L-DOPA (7.5 mg/kg po) increased locomotor activity and decrease disability scores in MPTP-treated common marmosets
  • bifeprunox (4 and 8 mg/kg po) also increased locomotor activity and decrease disability scores.
  • bifeprunox (4 or 8 mg/kg po) tended to increase total locomotor activity and locomotor 'On-Time' compared to L-DOPA alone.
  • compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art.
  • the compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer.
  • the pharmaceutical formulation contains at least one preparation of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • the total amount of active ingredients suitably is in the range of from about 0.1 % (w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50% (w/w) and preferably from 1 % to 25% (w/w).
  • the molar ratio between bifeprunox (or its N-oxide) and L-DOPA may be in the range of from about 1000:1 to about 1 :1000, suitably lies in the range of from 300:1 to 1 :300, and preferably from 50:1 to 1 :50.
  • preparations of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
  • auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
  • auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • the mixture may then be processed into granules or pressed into tablets.
  • the active ingredients may be separately premixed with the other non-active ingredients, before being mixed to form a formulation.
  • the active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain granules of the active ingredients.
  • Hard gelatine capsules may also contain the active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents.
  • Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use.
  • formulations and 'kits of parts' comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy.
  • container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
  • formulations of the present invention in the manufacture of medicaments for use in treating a condition in which recovery of dopaminergic function is required or desired, and methods of medical treatment or comprising the administration of a therapeutically effective total amount of at least one preparation of the invention to a patient suffering from, or susceptible to, a condition in which recovery of dopaminergic function is required or desired.
  • Figure 1 The effect of bifeprunox (4 mg/kg/ p.o.) alone or in combination with L-DOPA (7.5 mg/kg p.o. on locomotor activity in MPTP treated common marmosets.
  • Figure 2 The effect of bifeprunox (8 mg/kg/ p.o.) alone or in combination with L-DOPA (7.5 mg/kg p.o. on locomotor activity in MPTP treated common marmosets.
  • Figure 3 The effect of bifeprunox (4 a activity) over 7 hours in MPTP treated common marmosets. * p,0.05 compared to Vehicle-Vehicle (Mann Whitney).
  • Figure 4 The effect of bifeprunox (4 or 8 mg/kg p.o.) alone or in combination with L-DOPA (7.5 mg/kg p.o.) on locomotor 'ON-Time' over 7 hours in MPTP treated common marmosets. * p ⁇ 0.05 compared to Vehicle-Vehicle (Mann Whitney).
  • Figure 5 The effect of bifeprunox (4 mg/kg/ p.o.) alone or in combination with L-DOPA (7.5 mg/kg p.o.) on disability score in MPTP treated common marmosets.
  • Figure 6 The effect of bifeprunox (8 mg/kg/ p.o.) alone or in combination with L-DOPA (7.5 mg/kg p.o.) on disability score in MPTP treated common marmosets.
  • Figure 7 The effect of bifeprunox (4 or 8 mg/kg/ p.o.) alone or in combination with L-DOPA (7.5 mg/kg p.o.) on total disability scores over 7 hours in MPTP treated common marmosets. * p ⁇ 0.05 compared to Vehicle-Vehicle (Mann Whitney).
  • Figure 8 The effect of bifeprunox (4 or 8 mg/kg/ p.o.) alone or in combination with L-DOPA (7.5 mg/kg p.o.) on total disability 'ON-Time' over 7 hours in MPTP treated common marmosets. * p ⁇ 0.05 compared to Vehicle-Vehicle (Mann Whitney).
  • Serotonin 5-HT 1A agonist improves motor complications in rodent and primate parkinsonian models. Neurology 57: 1829-1834;

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Neurology (AREA)
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  • Psychology (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une préparation combinée de bifeprunox ou de son N-oxyde, ou de sels pharmacologiquement acceptables de ces composés : et de L-DOPA, lesquels seront utilisés simultanément, indépendamment ou séquentiellement pour le traitement de troubles requérant la récupération de la fonction dopaminergique, en particulier la maladie de Parkinson et le syndrome des jambes sans repos.
PCT/EP2007/055956 2006-06-16 2007-06-15 Préparations combinées contenant du bifeprunox et de la l-dopa WO2007144422A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2009514810A JP2009539942A (ja) 2006-06-16 2007-06-15 ビフェプルノックス及びｌ−ｄｏｐａを含む組み合わせ製剤
CA002654557A CA2654557A1 (fr) 2006-06-16 2007-06-15 Preparations combinees contenant du bifeprunox et de la l-dopa
EA200970022A EA014576B1 (ru) 2006-06-16 2007-06-15 Комбинированные препараты, содержащие бифепрунокс и l-допу
BRPI0713691-9A BRPI0713691A2 (pt) 2006-06-16 2007-06-15 preparação combinada, uso de um preparação, composição farmacêutica, e, método de tratar um distúrbio
EP07730194A EP2037964A2 (fr) 2006-06-16 2007-06-15 Preparation combinees contenant du bifeprunox et un agoniste de la dopamine
MX2008016226A MX2008016226A (es) 2006-06-16 2007-06-15 Preparaciones de combinacion que comprenden bifeprunox y l-dopa.
AU2007259256A AU2007259256A1 (en) 2006-06-16 2007-06-15 Combination preparations comprising bifeprunox and L-DOPA
IL195493A IL195493A0 (en) 2006-06-16 2008-11-25 Combination preparations comprising bifeprunox and l-dopa
NO20090165A NO20090165L (no) 2006-06-16 2009-01-12 Kombinasjonsfremstillinger innbefattende bifeprunox og L-DOPA

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US81405206P 2006-06-16 2006-06-16
EP06115587.5 2006-06-16
EP06115587 2006-06-16
US60/814,052 2006-06-16

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WO2007144422A2 true WO2007144422A2 (fr) 2007-12-21
WO2007144422A3 WO2007144422A3 (fr) 2008-03-13

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JP (1) JP2009539942A (fr)
KR (1) KR20090033871A (fr)
AU (1) AU2007259256A1 (fr)
CA (1) CA2654557A1 (fr)
EA (1) EA014576B1 (fr)
IL (1) IL195493A0 (fr)
NO (1) NO20090165L (fr)
WO (1) WO2007144422A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20100260A1 (it) * 2010-02-19 2011-08-20 Giulio Scigliano Composizione farmaceutica contenente un farmaco per ridurre gli effetti collaterali dei farmaci antipsicotici
JP2011526596A (ja) * 2008-06-30 2011-10-13 ノバルティス アーゲー 組み合わせ製品
RU2611376C2 (ru) * 2010-10-15 2017-02-21 Контера Фарма Апс Фармацевтическая композиция для лечения, профилактики или облегчения двигательных расстройств и ее применение
US10561618B2 (en) 2012-04-18 2020-02-18 Contera Pharma Aps Orally available pharmaceutical formulation suitable for improved management of movement disorders
US11975104B2 (en) 2016-07-11 2024-05-07 Contera Pharma A/S Pulsatile drug delivery system for treating morning akinesia

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT3209302T (pt) 2014-10-21 2019-07-19 Abbvie Inc Profármacos de carbidopa e l-dopa e a sua utilização para tratar doença de parkinson

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR045362A1 (es) * 2003-08-18 2005-10-26 Solvay Pharm Bv Forma cristalina estable de mesilato de bifeprunox (monometansulfonato de 7-[4-([1,1- bifenil] -3- ilmetil) -1- piperazinil] - 2-(3h) -benzoxazolona

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011526596A (ja) * 2008-06-30 2011-10-13 ノバルティス アーゲー 組み合わせ製品
ITMI20100260A1 (it) * 2010-02-19 2011-08-20 Giulio Scigliano Composizione farmaceutica contenente un farmaco per ridurre gli effetti collaterali dei farmaci antipsicotici
WO2011101799A1 (fr) * 2010-02-19 2011-08-25 Giulio Scigliano Compositions pharmaceutiques destinées à une utilisation dans des thérapies pour troubles psychiatriques
RU2611376C2 (ru) * 2010-10-15 2017-02-21 Контера Фарма Апс Фармацевтическая композиция для лечения, профилактики или облегчения двигательных расстройств и ее применение
US10561618B2 (en) 2012-04-18 2020-02-18 Contera Pharma Aps Orally available pharmaceutical formulation suitable for improved management of movement disorders
US11975104B2 (en) 2016-07-11 2024-05-07 Contera Pharma A/S Pulsatile drug delivery system for treating morning akinesia

Also Published As

Publication number Publication date
CA2654557A1 (fr) 2007-12-21
IL195493A0 (en) 2009-09-01
EA200970022A1 (ru) 2009-06-30
WO2007144422A3 (fr) 2008-03-13
EP2037964A2 (fr) 2009-03-25
JP2009539942A (ja) 2009-11-19
KR20090033871A (ko) 2009-04-06
NO20090165L (no) 2009-01-12
AU2007259256A1 (en) 2007-12-21
EA014576B1 (ru) 2010-12-30

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