EP2035002A1 - Kombinationspräparate mit slv308 und einem l-dopa - Google Patents

Kombinationspräparate mit slv308 und einem l-dopa

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Publication number
EP2035002A1
EP2035002A1 EP07730193A EP07730193A EP2035002A1 EP 2035002 A1 EP2035002 A1 EP 2035002A1 EP 07730193 A EP07730193 A EP 07730193A EP 07730193 A EP07730193 A EP 07730193A EP 2035002 A1 EP2035002 A1 EP 2035002A1
Authority
EP
European Patent Office
Prior art keywords
slv308
dopa
treatment
disease
preparation
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP07730193A
Other languages
English (en)
French (fr)
Inventor
Andrew C. Mccreary
Gustaaf J.M. Van Scharrenburg
Martinus Th. M. Tulp
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Healthcare Products BV
Original Assignee
Solvay Pharmaceuticals BV
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Filing date
Publication date
Application filed by Solvay Pharmaceuticals BV filed Critical Solvay Pharmaceuticals BV
Priority to EP07730193A priority Critical patent/EP2035002A1/de
Publication of EP2035002A1 publication Critical patent/EP2035002A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Example 3 Pharmaceutical preparations 13 Legends to the Figures 1 - 7 15
  • the invention concerns the use of a combination preparation of SLV308 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.
  • full dopamine receptor agonists such as apomorphine, bromocryptine, lisuride, pergolide, pramipexol or ropinirole
  • They prime for dyskinesias induce psychotic-like symptoms including hallucinations, orthostatic hypotension, somnolence, and other side-effects ⁇ Lozano, 1998; Bennett, 1999). It has been suggested that this could be overcome by using partial dopamine D 2 /3 receptor agonists (i.e. compounds that do not maximally stimulate dopamine D m receptors) (Jenner 2002).
  • Such compounds would hypothetically be capable of stimulating dopamine D 2/3 receptors when the dopaminergic tone is low, while being able to counteract excessive stimulation of the dopamine D 2 receptor when the dopaminergic tone is high, thereby resulting in "stabilisation” of dopaminergic transmission in the brain (Jenner, 2002).
  • 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 (Kannari, 2002) and haloperidol-induced extrapyramidal side effects in primates (Christoffersen, 1998). More recently it has been suggested that sarizotan, a 5-HT 1A receptor agonist and dopamine receptor ligand, could ameliorate dyskinetic symptoms ⁇ Olanow, 2004; Bara-Jimenez, 2005; Bibbiani, 2001). The presence of 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-DOPA's 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-DOPA's 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). Despite changes in their treatment regimes, 15-20% of patients find that all medications are inadequate because of adverse effects and limited treatment benefit
  • SLV308 combines high potency partial agonism at dopamine D 2/3 receptors (acting as a dopamine stabiliser) with full efficacy low potency serotonin 5-HT 1A receptor agonism.
  • WO 00/29397 Feenstra, 2001; Johnston, 2001 a b ; Hesselink, 2001, 2003, McCreary, 2001, 2006; Wolf, 2003.
  • WO 2007/023141 it was disclosed that in vivo the N-oxide of SLV308 is rapidly converted to SLV308, thus functioning as 'prodrug'.
  • 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.
  • L-DOPA Long Term Evolution
  • SLV308 reduced peak locomotor activity as observed after L-DOPA alone, such that hyperactivity was not observed.
  • the duration of activity ("on"-time) following L-DOPA was increased by coadministration of SLV308.
  • the subject matter of the invention are combination preparations of SLV308 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 SLV308 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:
  • kits of parts comprising:
  • a vessel containing L-DOPA optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, and:
  • 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: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
  • 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:
  • SLV308 its N-oxide, or pharmacologically acceptable salts, hydrates and solvates thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in conjunction with: (ii) L-DOPA, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • 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 To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about”.
  • 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 SLV308 and other medicaments physically combined in one preparation such as a tablet or injection fluid, as well as 'kit-of-parts', comprising SLV308 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 includes that respective formulations comprising SLV308 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. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition, will depend upon the condition to be treated or prevented, but may be achieved routinely by the person skilled in the art.
  • 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.
  • administered simultaneously and “administered at the same time as” include that individual doses of SLV308 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.
  • EXAMPLE 1 Interaction between SLV308 and L-DOPA at therapeutically relevant doses
  • SLV308 was dissolved in 10% sucrose and given in a volume of 2 ml/kg and administered by oral gavage. Doses are expressed as mg/kg free base.
  • L-DOPA methyl ester (Sigma, UK) was dissolved in 10% sucrose in given in a volume of 2 ml/kg and administered by oral gavage.
  • Carbidopa (Merck Sharp and Dohme, UK) was suspended in 10% sucrose in given in a volume of 2 ml/kg and administered directly into the mouth of the animal.
  • Domperidone (Sigma, UK) was suspended in 10% sucrose in given in a volume of 2 ml/kg and administered directly into the mouth of the animal.
  • Doses were based on a previous study with SLV308 in which it was shown that the optimal effect of SLV308 on locomotor activity and disability scores was achieved at 0.26 mg/kg, po. Doses of L-DOPA were chosen to reflect a moderate and high dose of L-DOPA (7.5 and 12.5 mg/kg, po respectively).
  • Locomotor activity was assessed as the number of light beam interruptions caused by movement of the animals accumulated in 10-minute intervals for up to 7 hours. The animals were allowed a 60-minute acclimatisation period in the activity cages during which baseline activity was assessed, before drug administration.
  • 'On' Threshold was defined as 3 times baseline activity in MPTP-treated marmosets. 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.
  • EXAMPLE 2 Effects of SLV308 on L-DOPA induced reversal of motor disabilities
  • Spontaneous Locomotor Activity SLV308 (0.26 mg/kg, po) increased locomotor activity within 30 minutes of administration ( Figure 1 ). Peak activity was seen 180 minutes after treatment and locomotor activity, and lasted for the 7 hour observation period. L-DOPA (7.5 and 12.5 mg/kg, po) produced an immediate increase in locomotor activity which peaked 60-90 min after administration ( Figure 1 and 2). The duration of activity was 150-240 min. Peak activity following L-DOPA (7.5 and 12.5 mg/kg, po) was greater than that seen following SLV308 (0.26 mg/kg, po) alone.
  • L-DOPA (7.5 and 12.5mg/kg po) produced an immediate reversal of disability that peaked at 90 minutes after administration, with a score of 2.5 ( Figure 5 and 6). The duration of this effect was 150 and 180 minutes for L-DOPA at 7.5 and 12.5mg/kg po, respectively.
  • 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 SLV308 (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.
  • 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.
  • Associated with such 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.
  • Arrow 1 SLV308 treatment, Arrow 2 L-DOPA treatment. Symbols: open squares vehicle group, filled squares L-DOPA 7.5 mg/kg po, open triangle SLV308 0.26 mg/kg po, and filled circles SLV308 followed by L-DOPA 7.5 mg/kg po.
  • Arrow 1 SLV308 treatment
  • Arrow 2 L-DOPA treatment Symbols: empty squares vehicle group, filled (black) squares: L-DOPA 12.5 mg/kg po, empty triangles SLV308 0.26 mg/kg po, and filled circles SLV308 followed by L-DOPA 12.5 mg/kg po.
  • Dashed lines Broken line- 'ON' threshold, Unbroken line-hyperactivity threshold. Error bars are omitted for clarity.
  • Arrow 1 SLV308 treatment
  • Arrow 2 L-DOPA treatment Symbols: empty squares vehicle group, filled squares L-DOPA (7.5 mg/kg, po), empty triangle SLV308 (0.26 mg/kg, po), and filled circles SLV308 followed by L-DOPA (7.5 mg/kg, po). Error bars are omitted for clarity.
  • Arrow 1 SLV308 treatment, arrow 2 L-DOPA treatment. Symbols: empty squares vehicle group, filled squares L-DOPA (12.5 mg/kg, po), empty triangles SLV308 (0.2 6mg/kg, po), and filled circles SLV308 followed by L-DOPA 12.5mg/kg po. Error bars are omitted for clarity.
  • Serotonin 5-HT 1A agonist improves motor complications in rodent and primate parkinsonian models. Neurology 57: 1829-1834;
  • Johnston, L. C, et al., 'SLV-308 Antiparkinsonian effects in the MPTP-treated common marmosets (Callithrix jacchus)' , Soc. Neurosci. Abstr., 27(1 ), page 531 , 2001 b .
  • PLM Periodic leg movements

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  • 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)
EP07730193A 2006-06-16 2007-06-15 Kombinationspräparate mit slv308 und einem l-dopa Withdrawn EP2035002A1 (de)

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EP07730193A EP2035002A1 (de) 2006-06-16 2007-06-15 Kombinationspräparate mit slv308 und einem l-dopa

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US81405106P 2006-06-16 2006-06-16
EP06115583 2006-06-16
EP07730193A EP2035002A1 (de) 2006-06-16 2007-06-15 Kombinationspräparate mit slv308 und einem l-dopa
PCT/EP2007/055955 WO2007144421A1 (en) 2006-06-16 2007-06-15 Combination preparations comprising slv308 and a l-dopa

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EP (1) EP2035002A1 (de)
JP (1) JP2009539941A (de)
KR (1) KR20090031908A (de)
AU (1) AU2007259255A1 (de)
CA (1) CA2654719A1 (de)
EA (1) EA015073B1 (de)
IL (1) IL195532A0 (de)
MY (1) MY148457A (de)
NO (1) NO20090164L (de)
WO (1) WO2007144421A1 (de)

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GB0027020D0 (en) 2000-11-03 2000-12-20 Univ Manchester Treatment of movement disorders
US20090247537A1 (en) * 2008-03-25 2009-10-01 William Dale Overfield Methods for preventing or treating bruxism using dopaminergic agents

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US7596407B2 (en) * 2004-03-26 2009-09-29 Solvay Pharmaceuticals, B.V. Transdermal iontophoretic delivery of piperazinyl-2(3H)-benzoxazolone compounds
PL1797871T3 (pl) * 2004-09-21 2015-07-31 Shandong luye pharmaceutical co ltd Długo działający preparat o przedłużonym uwalnianiu zawierający agonistę receptora dopaminowego i sposób jego wytwarzania
PT1919883E (pt) * 2005-08-22 2009-03-26 Solvay Pharm Bv N-óxidos como pró-medicamentos de derivados de piperazina & piperidina

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KR20090031908A (ko) 2009-03-30
EA200970021A1 (ru) 2009-06-30
AU2007259255A1 (en) 2007-12-21
MY148457A (en) 2013-04-30
CA2654719A1 (en) 2007-12-21
NO20090164L (no) 2009-01-14
JP2009539941A (ja) 2009-11-19
WO2007144421A1 (en) 2007-12-21
IL195532A0 (en) 2009-09-01
EA015073B1 (ru) 2011-04-29

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