WO2017152974A1 - Comprimé multicouche de mazindol à libération immédiate/libération prolongée pour le traitement du trouble déficitaire de l'attention avec hyperactivité (tdah) - Google Patents

Comprimé multicouche de mazindol à libération immédiate/libération prolongée pour le traitement du trouble déficitaire de l'attention avec hyperactivité (tdah) Download PDF

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Publication number
WO2017152974A1
WO2017152974A1 PCT/EP2016/055048 EP2016055048W WO2017152974A1 WO 2017152974 A1 WO2017152974 A1 WO 2017152974A1 EP 2016055048 W EP2016055048 W EP 2016055048W WO 2017152974 A1 WO2017152974 A1 WO 2017152974A1
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WO
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Prior art keywords
dosage form
unit dosage
mazindol
cellulose
form according
Prior art date
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PCT/EP2016/055048
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English (en)
Inventor
Alexander C. ZWYER
Lewis P. AMSEL
Virginia SCHMITH
Scott BRANTLEY
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Nls-1 Pharma Ag
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Priority to PCT/EP2016/055048 priority Critical patent/WO2017152974A1/fr
Priority to ES17724102T priority patent/ES2884973T3/es
Priority to BR112018068143A priority patent/BR112018068143A2/pt
Priority to PL17724102T priority patent/PL3426232T3/pl
Priority to MA045840A priority patent/MA45840A/fr
Priority to MX2018010864A priority patent/MX2018010864A/es
Priority to KR1020187028626A priority patent/KR102304743B1/ko
Priority to CN202310749459.0A priority patent/CN116803379A/zh
Priority to EP21177251.2A priority patent/EP3928770A1/fr
Priority to PT177241023T priority patent/PT3426232T/pt
Priority to CN201780028569.0A priority patent/CN109152740A/zh
Priority to IL295519A priority patent/IL295519A/en
Priority to EP17724102.3A priority patent/EP3426232B1/fr
Priority to NZ745921A priority patent/NZ745921A/en
Priority to IL261418A priority patent/IL261418B/en
Priority to JP2018546837A priority patent/JP7127832B2/ja
Priority to MA055045A priority patent/MA55045A/fr
Priority to PCT/IB2017/000352 priority patent/WO2017153846A2/fr
Priority to AU2017230974A priority patent/AU2017230974B2/en
Priority to CA3016852A priority patent/CA3016852C/fr
Priority to US16/083,131 priority patent/US11207271B2/en
Publication of WO2017152974A1 publication Critical patent/WO2017152974A1/fr
Priority to US17/538,333 priority patent/US20220160639A1/en
Priority to AU2022202771A priority patent/AU2022202771A1/en
Priority to JP2022127603A priority patent/JP7504488B2/ja
Priority to US18/409,041 priority patent/US20240165034A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • ADHD Attention Deficit/Hyperactivity Disorder
  • the present invention relates to a modified-release composition of mazindol and its use in the treatment of attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alertness (i.e, incoercible sleepiness) or decline of vigilance (i.e., daytime somnolence) or excessive daytime sleepiness (eg, narcolepsy, idiopathic hypersomnia) in particular in children, adolescents and adults.
  • ADHD is a behavioural disorder that constitutes one of the most frequently encountered patterns in child and adolescent psychopathology. It is also present in adults.
  • the stimulents used, and commonly accepted in the pharmacological treatment of ADHD belong to several pharmacological classes: psychostimulants (amphetamine, methylphenidate), eugregorics (armodafinil, modafinil, adrafinil), and inhibitors of monoamine oxydase B (selegiline).
  • psychostimulants amphetamine, methylphenidate
  • eugregorics armodafinil, modafinil, adrafinil
  • inhibitors of monoamine oxydase B serlegiline
  • Stimulants e.g., methylphenidate or amphetamines salts
  • Stimulants are associated with the appearance of "on-off effects, where the coming-off effect is accompanied by a "symptom rebound” effect with a worsening of the symptoms in the early evening (e.g., a time when homework needs to be completed).
  • mazindol in treatment of attention deficit/hyperactivity disorder (ADHD), according to DSM-IV (or DSM-V) criteria, comprising administering an effective amount of mazindol to a patient in need of such treatment has been described in US 8,293,779.
  • Mazindol is considered, in current medication classifications, as a psycho analeptic and anorexigenic medication, but also as giving rise to wakefulness, currently not authorised in France, or only authorised by TAU (Temporary Authorisation for Use) in obesity and narcolepsy. It is currently authorized in Argentina, Mexico/Central America, and Japan for use in the treatment of obesity. It is an advantageous chemical compound for dealing with malfunctioning of wakefulness mechanisms.
  • mazindol The essential pharmacological action of mazindol, in all species studied, in healthy animals and in humans, is hypothalamic, on the appetite-regulating dopaminergic centres (Hadler, 1972). It is metabolized extensively and the metabolites are then mostly excreted in the urine.
  • mazindol is a non-amphetamine compound because of its tricyclic chemical structure. It offers a pharmacological profile very close to that of amphetamines with less abuse liability. Indeed, mazindol is not metabolised to an amphetamine -like compound, but it acts by blocking the dopamine and norepinephrine reuptake similarly to amphetamine.
  • immediate -release pharmaceutical compositions of mazindol have been reported to undergo hydrolysis at moderate temperatures in neutral and alkaline aqueous solutions, including in human plasma. Due to the mild alkaline nature of plasma, improved mazindol stability in human plasma could be achieved by adding acidic buffer.
  • Such immediate release compositions thus require twice daily administration, which limits compliance in the special case of children of school age, as the second administration is often requested to be done at midday, i.e. during school time.
  • Tmax time to maximum concentrations
  • a controlled release portion would also be needed to assure that adequate plasma concentrations are achieved throughout the day and evening, while allowing the subject to fall asleep and remain asleep during the night.
  • a combination product consisting of an immediate release portion (IR) and a sustained release portion (SR) would be an ideal dose form.
  • the present invention thus relates to a mazindol oral pharmaceutical unit dosage form in the form of a multilayer matrix-type tablet comprising:
  • At least one immediate -release (IR) layer comprising mazindol and at least one diluent
  • at least one sustained-release (SR) layer comprising mazindol and at least one sustained-release, pH-independent and water-insoluble polymer
  • a total amount of mazindol comprised between 1 and 5 mg and a ratio in weight between the IR layers and the SR layers comprised between 40:60 and 80:20 preferably between 50:50 and 70:30, more preferably of 50:50.
  • the oral pharmaceutical unit dosage form in the form of a multilayer matrix-type tablet of the invention provides a rapid release of drug to achieve a rapid therapeutic blood level and a sustained release portion to provide a continual release of mazindol available for absorption into the patients' blood stream to achieve a prolonged therapeutic effect. This combination thus achieves a once daily regimen for the product.
  • This oral pharmaceutical unit dosage form has the following advantages:
  • the invention relates to a process for preparing the unit dosage form according to the invention, comprising the following steps:
  • step (b) adding the IR blend of step (a) and the SR blend of step (a') into a multilayer, preferably a bilayer, tablets' press.
  • the invention relates to the unit dosage form according to the invention, for its use as medicinal product administered in repeat once-a-day form via oral route.
  • the invention relates to the unit dosage form according to the invention, for use for treating attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alerteness (i.e, incoercible sleepiness) or decline of vigilance (i.e., daytime somnolence) or excessive daytime sleepiness (eg, narcolepsy, idiopathic hypersomnia) in particular in children, adolescents and adults.
  • ADD attention deficit disorders
  • ADHD attention deficit/hyperactivity disorder
  • related deficit of alerteness i.e, incoercible sleepiness
  • decline of vigilance i.e., daytime somnolence
  • excessive daytime sleepiness eg, narcolepsy, idiopathic hypersomnia
  • the invention relates to a method for treating attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alerteness (i.e, incoercible sleepiness) or decline of vigilance (i.e., daytime somnolence) or excessive daytime sleepiness (eg, narcolepsy, idiopathic hypersomnia) comprising the administration, preferably in repeat once-a-day via oral route, of the unit dosage form according to the invention to a patient in need thereof, in particular in children, adolescents and adults.
  • ADD attention deficit disorders
  • ADHD attention deficit/hyperactivity disorder
  • related deficit of alerteness i.e, incoercible sleepiness
  • decline of vigilance i.e., daytime somnolence
  • excessive daytime sleepiness eg, narcolepsy, idiopathic hypersomnia
  • the invention relates to the unit dosage form according to the invention, used in combination with iron as a combination product for simultaneous, separate or sequential use, in particular for treating attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alertness (i.e, incoercible sleepiness) or decline of vigilance (i.e., daytime somnolence) or excessive daytime sleepiness (eg, narcolepsy, idiopathic hypersomnia) in particular in children, adolescents and adults.
  • ADD attention deficit disorders
  • ADHD attention deficit/hyperactivity disorder
  • related deficit of alertness i.e, incoercible sleepiness
  • decline of vigilance i.e., daytime somnolence
  • excessive daytime sleepiness eg, narcolepsy, idiopathic hypersomnia
  • the invention relates to a method for treating attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alerteness (i.e, incoercible sleepiness) or decline of vigilance (i.e., daytime somnolence) or excessive daytime sleepiness (eg, narcolepsy, idiopathic hypersomnia) comprising the administration, preferably in repeat once-a-day via oral route, of the unit dosage form according to the invention and the administration of iron to a patient in need thereof, in particular in children, adolescents and adults.
  • ADD attention deficit disorders
  • ADHD attention deficit/hyperactivity disorder
  • related deficit of alerteness i.e, incoercible sleepiness
  • decline of vigilance i.e., daytime somnolence
  • excessive daytime sleepiness eg, narcolepsy, idiopathic hypersomnia
  • the invention relates to the unit dosage form according to the invention, used in combination with a psychostimulant as a combination product for simultaneous, separate or sequential use, in particular for treating attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alerteness (i.e, incoercible sleepiness) or decline of vigilance (i.e., daytime somnolence) or excessive daytime sleepiness (eg, narcolepsy, idiopathic hypersomnia) in particular in children, adolescents and adults.
  • ADD attention deficit disorders
  • ADHD attention deficit/hyperactivity disorder
  • related deficit of alerteness i.e, incoercible sleepiness
  • decline of vigilance i.e., daytime somnolence
  • excessive daytime sleepiness eg, narcolepsy, idiopathic hypersomnia
  • the invention relates to a method for treating attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alerteness (i.e, incoercible sleepiness) or decline of vigilance (i.e., daytime somnolence) or excessive daytime sleepiness (eg, narcolepsy, idiopathic hypersomnia) comprising the administration, preferably in repeat once-a-day, via oral route of the unit dosage form according to the invention and the administration of a psychostimulant to a patient in need thereof, in particular in children, adolescents and adults.
  • ADD attention deficit disorders
  • ADHD attention deficit/hyperactivity disorder
  • related deficit of alerteness i.e, incoercible sleepiness
  • decline of vigilance i.e., daytime somnolence
  • excessive daytime sleepiness eg, narcolepsy, idiopathic hypersomnia
  • matrix-type tablet is used in the invention to designate a tablet whose inner structure in each layer is homogeneous and identical from the center towards the periphery of the layer. Therefore, the layers of the tablets of the present invention consist of a homogeneous mixture of active ingredient in powder or granule form and of a compression matrix.
  • compression matrix in the present invention is used to designate all the excipients which take part in the cohesion of the tablet.
  • Said compression matrix is both water-insoluble and has a certain permeability (hydrophilic matrix) or porous network (inert matrix) responsible for the sustained release of the active ingredient, which does not vary in relation to the pH conditions of the medium.
  • compression mixture is used in the present application to designate all the constituents of the tablets (the active ingredient(s), granulated or not, and the constituents of the compression matrix) before its compression in tablet form.
  • steady-state refers to the concentrations in the body after 4 to 7 half-lives after repeat dosing.
  • concentrations at steady-state differ depending on the formulation used and the dosing frequency.
  • plasma concentrations of mazindol will vary between Cmax(ss) (the maximum observed concentration at steady-state) and Cmin(ss) (the minimum observed concentration at steady-state).
  • a study with repeat doses not only provides a measure of the usual pharmacokinetic parameters (area under the curve during a dosing interval at steady-state, AUC(O-x), Cmax(ss), the time to the Cmax or Cmax(ss), Tmax), but also demonstrates the significance of the fluctuations between the steady-state peak (Cmax(ss)) and trough (Cmin(ss)) concentrations.
  • Tmax is the time to reach the peak concentration. This value is dependent on the absorption rate of a pharmaceutically active material.
  • the expression « reduction of fluctuations » may designate the lowering of the difference between the Cmax(SS) and Cmin(SS) or differences between the peaks and troughs, or preferably a value for the « fluctuation » parameter of between 25 % and 75 % in one embodiment, ⁇ 60% in one embodiment, ⁇ 50% in one embodiment, or more preferably less than 35 %.
  • the half-life (t1 ⁇ 2) is the time for a concentration C of a drug in a body fluid or a tissue to reach the concentration C/2.
  • AUC(O-x) The area under the curve during a dosing interval at stead-state, AUC(O-x), corresponds to the integral of the plasma concentration over a given dosing interval.
  • the AUC(O-x) is expressed in units of mass (mg, ng) x liter (or mL) "1 x hour, and is dependent on the bioavailability and clearance of a drug.
  • a profile having « reduced fluctuation » is meant a profile having a swing ⁇ of less than 50 % in one embodiment or ⁇ 60% in one embodiment, or ⁇ 35% in one embodiment.
  • a profile having « reduced fluctuation » is also meant a plasma profile maintained above 40 % or preferably above 50 % of the Cmax(SS) value for at least 12 hours.
  • An “immediate-release (IR) layer” refers to a layer that releases greater than or equal to about 80% by weight of mazindol in less than or equal to about 1 hour.
  • a "sustained-release (SR) layer” means a layer in which mazindol is released at a rate slower than that of an IR layer.
  • Figures 1 - 6 depict dissolution profiles of the prototype tablets of Example 3.
  • Figure-6 Overlay of Dissolution Profiles for 70/30 IR/SR Ratio Tablet Formulations
  • Figure-7 Overlay of Dissolution Profiles from Batch 100-15021 Tablets Analyzed Using UV Probes (100-15021) and HPLC Analysis (15021LC)
  • Figure-8 Overlay of Dissolution Profiles from Batch 100-15022 Tablets Analyzed Using UV Probes (100-15022) and HPLC Analysis (15022LC)
  • the pharmaceutical composition according to the present invention is a mazindol oral pharmaceutical unit dosage form in the form of a multilayer matrix-type tablet comprising:
  • IR immediate-release
  • SR sustained-release layer comprising mazindol and at least one sustained-release, pH-independent and water-insoluble polymer
  • a total amount of mazindol comprised between 1 and 5 mg and a ratio in weight between the IR layers and the SR layers comprised between 40:60 and 80:20 preferably between 50:50 and 70:30, more preferably of 50:50.
  • the unit dosage form according to the invention is a bilayer tablet.
  • the unit dosage form according to the invention has a dissolution of between 60% and 80% at 1 hour, of between 70% and 90% at 2 hours, as measured in accordance with the rotating blade method at 50 rpm according to the US Pharmacopeia Method 2, in a dissolution medium 0.01N HC1, 500 mL.
  • the unit dosage form according to the invention is of between 50 and 200 mg, preferably of 100 mg.
  • the unit dosage form according to the invention comprises between 2 and 5 mg of mazindol, preferably of 4 mg.
  • the unit dosage form according to the invention maintains the steady-state mazindol plasma concentrations obtained in vivo with a reduced fluctuation of above 40 % of the CsSmax value, preferably above 50 % of the Css max value for at least 12 h.
  • diluents include: lactose, monohydrate lactose, anhydrous lactose, spray-dried lactose, calcium carbonate, calcium sulfate, calcium sulfate dehydrate, calcium lactate trihydrate, monobasic calcium sulfate monohydrate, calcium carbonate, tribasic calcium phosphate, diabasic calcium phosphate, compressible sugars, dextrates, dextrin, dextrose, calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered cellulose, starch, modified starch, starch hydrolyzates, pregelatinized starch, microcrystalline cellulose, powdered cellulose, cellulose and cellulose derivatives, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose and sucrose, preferably lactose, anhydrous lactose, spray-dried lactose, microcrystalline cellulose, powdered cellulose, cellulose and cellulose derivatives.
  • Diluent concentration in the IR layers can be varied between 30 and 60%, preferably 45 to 55% by weight of the total weight of the IR layers.
  • the unit dosage form according to the invention comprises a lubricant in each layer.
  • Lubricants and glidants can be employed in the present application to prevent, reduce or inhibit adhesion or friction of ingredients of the composition. They facilitate the compression and ejection of compressed compositions from a desired die. They are compatible with the ingredients of the pharmaceutical composition, and they do not significantly reduce the solubility, hardness, chemical stability, physical stability, or the biological activity of the pharmaceutical composition.
  • the pharmaceutically acceptable lubricants and glidants for the present application are selected from the group including but not limited to stearic acid, metallic stearates, zinc stearate, magnesium stearate, magnesium trisilicate, calcium hydroxide, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium stearate, glyceryl monostearate, waxes, glycerides, glyceryl behenate, glyceryl palmitostearate, silicone oil, hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, mineral oil, polyethylene glycol, methoxypolyethylene glycol, sodium acetate, sodium oleate, sodium chloride, leucine, sodium benzoate, alkyl sulfates, sodium lauryl sulfate, sodium stearyl fumarate, talc, colloidal silica, corn starch, powdered cellulose, and/or boric acid.
  • stearic acid metallic stearates, zinc
  • the preferred range of lubricants/glidants is from 0% to 1% w/w of the layer.
  • the sustained-release, pH-independent and water-insoluble polymer in SR layers of the tablets according to the invention is selected in the group consisting of cellulose polymers, high-molecular-weight polymers of acrylic acid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol (Carbopol, Carbomers), polymers from the class of methacrylic acids, polyvinylalcohol derivatives, polymers of lactic and glycolic acids (PLGA), starches, waxes, polyvinyl acetate derivatives, polyvinyl pyrrolidone derivatives and mixtures thereof, preferably is selected in the group consisting of cellulose polymers and high-molecular- weight polymers of acrylic acid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol (Carbopol, Carbomers).
  • Cellulose polymers include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium CMC, ethyl cellulose derivatives such as cellulose acetate, cellulose acetate butyrate, cellulose acetate cellulose propionate, hydroxypropylmethylcellulose acetate succinate, micro crystalline cellulose (for example such as the one supplied under the trade mark Avicel®, and ethylcellulose (for example the one supplied under the trade mark Aqualon® ethylcellulose)
  • Polymers from the class of methacrylic acids include the grades Eudragit®RL 12.5, RL PO and RL 100 and RS 12.5, RS PO and RS 100.
  • Starches include natural starches e.g. corn starches and modified starches such as pre-gelled starch,
  • Waxes include white or yellow beeswax, polyvinyl acetate derivatives.
  • Sustained-release, pH-independent and water-insoluble polymer concentration in the SR layers can be varied between 80 and 99%, preferably 90 to 97% by weight of the total weight of the SR layers.
  • the unit dosage form according to the invention can include anti-agglomerant agents, anti-agglomerant agents used in the present invention include talc, silicon dioxide and its derivatives, acrylic esters, castor oil derivative, cellulose compounds, iron oxides, magnesium stearate, stearic acid and or sodium stearate fumaryl.
  • Layers of the tablet according to the present invention can comprise a binder.
  • Binders according to the invention include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), maltodextrin, polyvinylpyrrolidone (PVP) and or micro crystalline cellulose.
  • the compression matrix can advantageously include, additionally to the excipients of the compression matrix, one or more excipients intended either to promote the proper conducting of the compression process.
  • the invention also relates to a process for preparing the unit dosage form according to the invention, comprising the following steps:
  • step (b) adding the IR blend of step (a) and the SR blend of step (a') into a multilayer, preferably a bilayer, tablets' press.
  • ADHD attention- deficit/hyperactivity disorder
  • ICD- 10 International Classification of Diseases (ICD). World Health Organization) and DSM-V (Diagnostic and Statistical Manual of Mental Disorders, 5 th edition).
  • the criteria of DSM-V includes three dimensions (inattention, impulsivity and hyperactivity), normal intellectual efficiency (IQ>80, with an age between 5 and 12 years) and having isolated iron deficiency, but not anaemic, that is to say having a normal haemoglobin level.
  • iron deficiency means hypoferrinaemia without significant modification to the serum concentration of soluble transferrin receptors.
  • ADHD symptom designates in particular attention disorders such as inattention, impulsivity, impatience, oppositional disorders, but also daytime or night-time motor hyperactivity, restless legs syndrome, and insomnia.
  • c. psychopathological insomnia generally chronic and generally linked to anxiety, stress and depressive episodes.
  • the criteria for evaluating the efficacy of the treatment of attention- deficit/hyperactivity disorder by of the modified-release pharmaceutical composition comprising mazindol optionally in association with iron and/or a psychostimulant in the treatment of attention-deficit/hyperactivity disorder according to the present invention are the reduction (>30%) in the rating scale severity score for attention-deficit/hyperactivity symptoms AHD-RS (after 12 weeks of treatment, and an improvement in severity scores for Conner's Parent questionnaire (CPRS), Conner's Teacher questionnaire (CTRS) and CGI (clinical global impressions).
  • Subjective somnolence is assessed using the CASS scale (child and adolescent somnolence scale).
  • the quality of falling asleep is assessed by means of the restless legs syndrome severity scale.
  • the patient according to the invention is chosen from among a newborn baby, a child, an adolescent and an adult. According to a preferred embodiment, the patient is a child or an adolescent or an adult, even more preferably a child aged approximately 5 to 12 years.
  • the patient according to the invention advantageously suffers iron deficiency, but is not anaemic. Ferritin deficiency can be measured in the serum, but also in all other biological fluids such as the cerebrospinal fluid.
  • a ferritin deficiency corresponds to a serum concentration of ferritin in the adult patient of less than approximately 50 ⁇ g/litre.
  • This deficit of iron storage (expressed by a low ferritin level) may reach ferritin concentrations of less than approximately 40 ⁇ g/l, or even less than approximately 35 ⁇ g/l, less than 30 ⁇ g/l, less than 20 ⁇ g/l, less than 15 ⁇ g/l, or even less than approximately 10 ⁇ g/l.
  • the techniques of determining serum ferritin are well known to persons skilled in the art.
  • the immunoenzymatic method IMX ferritin kit, Abbot Laboratories
  • the patient according to the invention also has a normal serum concentration of receptors soluble to transferrin.
  • Transferrin is involved in the acquisition of iron by the cells of the organism; this acquisition is controlled by the number of transferrin receptors existing on the cell surface.
  • concentration of these receptors can be evaluated by techniques known to persons skilled in the art such as nephelemetry (Ruivard et al. 2000 Rev Med Interne 21 : 837-843).
  • a normal range of concentration of receptors soluble to transferrin is 2.0-4.50 mg/1 for men and 1.80-4.70 mg/1 for women (see RsTF kit Ref 2148315 from Roche).
  • mazindol is used in combination with iron as a combination product for simultaneous, separate or sequential use.
  • the iron is used as a supplement with the patient before the administration of mazindol.
  • iron means iron in the form of an iron atom, iron salt or organic iron, or any formulation containing iron that is pharmaceutically acceptable.
  • the pharmaceutically acceptable iron salt is selected from ferrous salts and ferric salts, preferably from ferric ammonium citrate, ferric pyrophosphate, ferrocholinate, ferrous abscorbate, ferrous aspartate, ferrous chloride, ferrous sulphate, ferrous tartrate, ferrous fumarate, ferrous gluconate, ferrous gluceptate, ferrous sulphate glycine, ferrous lactate, ferrous oxalate and ferrous succinate.
  • the iron salt is ferrous sulphate, and preferably gastro -protected ferrous sulphate.
  • the pharmaceutical acceptable iron is in the form of dextran iron, sucrose iron, poly-maltose iron, or sorbitol iron.
  • the iron is in the form of pharmaceutically acceptable organic iron, it is preferably iron biglycinate, iron glycinate or iron protein succinylate.
  • mazindol possibly in association with the iron according to the invention is implemented in combination with at least one compound selected from psychostimulants, as a combination product for simultaneous, separate or sequential use.
  • Psychostimulant compounds designate dopamine and/or noradrenaline uptake inhibitors and agonists of catecholamines. Among these, the following can be cited non- exhaustively:
  • the quantity of ferrous sulphate administered to the patient on a daily basis is between 0.1 mg and 10 mg, preferably between 100 mg and 2 g per day, preferably approximately 500 mg, in one or more doses.
  • the patients undergo iron supplementation, in particular ferrous sulphate, for 12 weeks and the treatment with mazindol for 12 weeks.
  • the composition may also comprise iron or one of its pharmaceutically acceptable salts and/or a psychostimulant.
  • Example 1 Conditions for the dissolution profiles:
  • Example 2 Process for manufacture of mazindol bilayer tablets
  • Example 3 Dissolution profiles of the bilayer tablets of example 2:
  • the bilayer tablet formulations are based on two sustained release (SR) formulations and one immediate release (IR) formulation.
  • IR SR 50/50, 60/40, & 70/30
  • Table-1 formulations include the SR formulation which utilizes HPMC and Carbopol 971P to modulate Mazindol dissolution and are categorized as Series 1 prototype formulations.
  • Table-2 formulations include the SR formulation which incorporates two different molecular weight grades of HPMC to modulate Mazindol dissolution and are categorized as Series 2 prototype formulations.
  • Table-3 reports the dissolution testing results for each of the prototype formulations.
  • Table-1 Series 1 Prototype Tablet Formulations
  • Lactose/HPMC K4M (Retalac ® ) 36.75 29.4 22.05
  • the dissolution data for the prototype tablets reveal the Series 1 formulations to have the greatest differentiation among the dissolution profiles at the early time points.
  • Kessler RC et al The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. American Journal of Psychiatry. 2006, 163(4):716-723.
  • Glatt SJ A comparison of the efficacy of medications for adult attention- deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry.
  • Antshel KM et al: Advances in understanding and treating ADHD. BMC Medicine.

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

La présente invention concerne une composition à libération modifiée de mazindol et son utilisation dans le traitement de troubles déficitaires de l'attention (TDA) ou du trouble déficitaire de l'attention avec hyperactivité (TDAH) ou de troubles apparentés tel un déficit de la vigilance (c'est-à-dire une somnolence incoercible) ou une baisse de la vigilance (c'est-à-dire une somnolence diurne) ou une somnolence diurne excessive (par exemple, une narcolepsie, une hypersomnie idiopathique), en particulier chez les enfants, les adolescents et les adultes.
PCT/EP2016/055048 2016-03-09 2016-03-09 Comprimé multicouche de mazindol à libération immédiate/libération prolongée pour le traitement du trouble déficitaire de l'attention avec hyperactivité (tdah) WO2017152974A1 (fr)

Priority Applications (25)

Application Number Priority Date Filing Date Title
PCT/EP2016/055048 WO2017152974A1 (fr) 2016-03-09 2016-03-09 Comprimé multicouche de mazindol à libération immédiate/libération prolongée pour le traitement du trouble déficitaire de l'attention avec hyperactivité (tdah)
IL295519A IL295519A (en) 2016-03-09 2017-03-08 Mazindol immediate-release/delayed-release multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder
IL261418A IL261418B (en) 2016-03-09 2017-03-08 Mazindol immediate-release/delayed-release multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder
NZ745921A NZ745921A (en) 2016-03-09 2017-03-08 A mazindol ir/sr multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (adhd)
MA045840A MA45840A (fr) 2016-03-09 2017-03-08 Comprimé multicouche de mazindol à libération immédiate/libération prolongée pour le traitement du trouble déficitaire de l'attention avec hyperactivité (tdah)
BR112018068143A BR112018068143A2 (pt) 2016-03-09 2017-03-08 forma farmacêutica unitária oral de mazindol na forma de comprimido do tipo multicamada e processo para preparar dita forma farmacêutica
KR1020187028626A KR102304743B1 (ko) 2016-03-09 2017-03-08 마진돌 ir/sr 다층 정제 및 그의 주의력 결핍/과잉행동 장애 (adhd)의 치료를 위한 용도
CN202310749459.0A CN116803379A (zh) 2016-03-09 2017-03-08 一种马吲哚即释/缓释多层片剂及其在治疗注意力缺失/多动障碍(adhd)中的用途
JP2018546837A JP7127832B2 (ja) 2016-03-09 2017-03-08 マジンドールのｉｒ／ｓｒ多層錠剤及び該錠剤の注意欠陥／多動性障害（ａｄｈｄ）の治療のための使用
PT177241023T PT3426232T (pt) 2016-03-09 2017-03-08 Comprimido multicamadas de mazindol ir/sr e a sua utilização para o tratamento do distúrbio de hiperatividade/défice de atenção (adhd)
CN201780028569.0A CN109152740A (zh) 2016-03-09 2017-03-08 一种马吲哚即释/缓释多层片剂及其在治疗注意力缺失/多动障碍(adhd)中的用途
ES17724102T ES2884973T3 (es) 2016-03-09 2017-03-08 Comprimido multicapa de mazindol de IR/SR y su utilización para el tratamiento del trastorno por déficit de atención/hiperactividad (ADHD)
EP17724102.3A EP3426232B1 (fr) 2016-03-09 2017-03-08 Comprimé multicouche de mazindol à libération immédiate/libération prolongée pour le traitement du trouble déficitaire de l'attention avec hyperactivité (tdah)
PL17724102T PL3426232T3 (pl) 2016-03-09 2017-03-08 Wielowarstwowa tabletka mazindol IR/SR i jej zastosowanie w leczeniu zespołu nadpobudliwości psychoruchowej z deficytem uwagi (ADHD)
MX2018010864A MX2018010864A (es) 2016-03-09 2017-03-08 Una tableta de capas multiples de liberacion inmediata/liberacion sostenida de mazindol y su uso para el tratamiento de deficit de la atencion/trastorno de hiperactividad (adhd).
EP21177251.2A EP3928770A1 (fr) 2016-03-09 2017-03-08 Comprimé multicouche de mazindol à libération immédiate/libération prolongée pour le traitement du trouble déficitaire de l'attention avec hyperactivité (tdah)
MA055045A MA55045A (fr) 2016-03-09 2017-03-08 Comprimé multicouche de mazindol à libération immédiate/libération prolongée pour le traitement du trouble déficitaire de l'attention avec hyperactivité (tdah)
PCT/IB2017/000352 WO2017153846A2 (fr) 2016-03-09 2017-03-08 Comprimé multicouche de mazindol à libération immédiate/libération prolongée pour le traitement du trouble déficitaire de l'attention avec hyperactivité (tdah)
AU2017230974A AU2017230974B2 (en) 2016-03-09 2017-03-08 A mazindol IR/SR multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (ADHD)
CA3016852A CA3016852C (fr) 2016-03-09 2017-03-08 Comprime multicouche de mazindol a liberation immediate/liberation prolongee pour le traitement du trouble deficitaire de l'attention avec hyperactivite (tdah)
US16/083,131 US11207271B2 (en) 2016-03-09 2017-03-08 Mazindol IR/SR multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (ADHD)
US17/538,333 US20220160639A1 (en) 2016-03-09 2021-11-30 Mazindol ir/sr multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (adhd)
AU2022202771A AU2022202771A1 (en) 2016-03-09 2022-04-27 A mazindol IR/SR multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (ADHD)
JP2022127603A JP7504488B2 (ja) 2016-03-09 2022-08-10 マジンドールのｉｒ／ｓｒ多層錠剤及び該錠剤の注意欠陥／多動性障害（ａｄｈｄ）の治療のための使用
US18/409,041 US20240165034A1 (en) 2016-03-09 2024-01-10 Mazindol ir/sr multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (adhd)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2016/055048 WO2017152974A1 (fr) 2016-03-09 2016-03-09 Comprimé multicouche de mazindol à libération immédiate/libération prolongée pour le traitement du trouble déficitaire de l'attention avec hyperactivité (tdah)

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WO2019137200A1 (fr) * 2018-01-09 2019-07-18 Triastek, Inc. Formes posologiques pour médicament à usage oral comprenant une dose fixe de non-stimulant du tdah et de stimulant du tdah
US11278499B2 (en) 2015-06-03 2022-03-22 Triastek, Inc. Oral drug dosage form comprising various release profiles
WO2024077180A1 (fr) * 2022-10-05 2024-04-11 Axsome Therapeutics, Inc. Utilisation du mazindol pour traiter des troubles du système nerveux

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11278499B2 (en) 2015-06-03 2022-03-22 Triastek, Inc. Oral drug dosage form comprising various release profiles
WO2019137200A1 (fr) * 2018-01-09 2019-07-18 Triastek, Inc. Formes posologiques pour médicament à usage oral comprenant une dose fixe de non-stimulant du tdah et de stimulant du tdah
US11571391B2 (en) 2018-01-09 2023-02-07 Triastek, Inc. Oral drug dosage forms compromising a fixed-dose of an ADHD non-stimulant and an ADHD stimulant
WO2024077180A1 (fr) * 2022-10-05 2024-04-11 Axsome Therapeutics, Inc. Utilisation du mazindol pour traiter des troubles du système nerveux

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