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WO1999003458A1 - Traitement de l'hyperactivite avec deficit de l'attention et de la narcolepsie - Google Patents

Traitement de l'hyperactivite avec deficit de l'attention et de la narcolepsie Download PDF

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Publication number
WO1999003458A1
WO1999003458A1 PCT/GB1998/002124 GB9802124W WO9903458A1 WO 1999003458 A1 WO1999003458 A1 WO 1999003458A1 GB 9802124 W GB9802124 W GB 9802124W WO 9903458 A1 WO9903458 A1 WO 9903458A1
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WO
WIPO (PCT)
Prior art keywords
selegiline
pharmaceutical composition
active ingredient
composition according
composition
Prior art date
Application number
PCT/GB1998/002124
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English (en)
Inventor
Edward Stewart Johnson
Original Assignee
R.P. Scherer Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by R.P. Scherer Limited filed Critical R.P. Scherer Limited
Priority to EP98967116A priority Critical patent/EP1028719A1/fr
Priority to AU16456/99A priority patent/AU1645699A/en
Publication of WO1999003458A1 publication Critical patent/WO1999003458A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • This invention relates to the use of a pharmaceutical composition for the manufacture of a medicament for the treatment of Attention Deficit Hyperactivity Disorder and/or narcolepsy and a method of treating these conditions.
  • ADHD Attention Deficit Hyperactivity Disorder
  • methylphenidate is often beneficially accompanied by behavioural education and psycho counseling.
  • Narcolepsy is a disorder characterised by uncontrollable sleepiness which begins in late childhood or adolescence. Several times a day, usually while sitting in class, the subject is overcome by an uncontrollable desire to sleep. Somnolence may occur in unusual situations, for instance, while standing or carrying on conversations. Also, in about 70% of patients cataplexy sometimes occurs. This is usually brought on by laughter (occasionally by excitement, sadness or anger) and causes the patient's head to fall forward, his jaw to drop, his knees to buckle, even with falling to the ground, all with perfect preservation of consciousness. Such attacks only last a minute or two. Sleep paralysis and hallucinations on waking may also occur but these are rare.
  • Methylphenidate acts on the brain in an analogous way to amphetamine, the 1-enantiomer (less active form) of which is produced by the liver as a metabolite of selegiline when administered orally in the form of a conventional tablet or syrup according to the following metabolic pathway:-
  • selegiline which is a monoamine oxidase B (MAO-B) inhibitor
  • MAO-B monoamine oxidase B
  • selegiline has been shown to be inactive clinically (see M. Ernst et al, Psychopharmacology Bulletin, (1996) , 3_2, 327-334) . It is believed that this is probably because lOmg conventional tablets administered daily give rise to too little 1-amphetamine to have any beneficial effect and the 20-60mg dose used by Ernst et al causes the inhibition of monoamine oxidase A (MAO-A) as well as MAO- B which reverses any potential beneficial effect.
  • MAO-A monoamine oxidase A
  • the preferred substrate for MAO-B is phenylethylamine, a chemical which occurs naturally in the brain. Phenylethylamine is structurally very closely related to amphetamine and is often referred to as the "endogenous amphetamine". It is known from WO 96/26720 that, if selegiline or, by implication, another MAO-B inhibiting compound which is susceptible to a high first pass effect is formulated in a composition to promote pre-gastric absorption of the MAO-B inhibitor, an increase in the amount of phenylethylamine occurs in the body to a far greater extent than with conventional oral formulations containing the same amount of active ingredient.
  • a pharmaceutical composition for oral administration comprising a carrier and, as an active ingredient, a monoamine oxidase B inhibitor characterised in that the composition is formulated to promote pre-gastric absorption of said monoamine oxidase B inhibitor, for the manufacture of a medicament for the treatment of Attention Deficit Hyperactivity Disorder and/or narcolepsy.
  • pre-gastric absorption is used to refer to absorption of the active ingredient from that part of the alimentary canal prior to the stomach and includes buccal, sublingual, oropharyngeal and oesophageal absorption.
  • compositions containing MAO-B inhibitors can be assessed using the method described for selegiline in Example 3 below. This test is similar to the "buccal absorption test" which is said by Harris and Robinson in a review article (J..Pharm. Sci., 1992, vol 81, p 1-10) to be a well recognised method for evaluating buccal absorption of drugs.
  • Harris and Robinson in a review article (J..Pharm. Sci., 1992, vol 81, p 1-10) to be a well recognised method for evaluating buccal absorption of drugs.
  • the test formulation containing the clinically effective dose of the MAO-B inhibitor is retained in the mouth for 1 minute before it is expectorated. The mouth is then rinsed with 3 aliquots of 25 ml of water which are similarly expectorated.
  • the total amount of MAO-B inhibitor is then determined in the expectorated mouth washings, using a suitable analytical technique such as HPLC, and the recovered quantity of MAO-B inhibitor is subtracted from the total amount of drug initially placed in the mouth to determine the total amount of drug which has been absorbed pre-gastrically .
  • a suitable analytical technique such as HPLC
  • the recovered quantity of MAO-B inhibitor is subtracted from the total amount of drug initially placed in the mouth to determine the total amount of drug which has been absorbed pre-gastrically .
  • at least 5% of the MAO-B inhibitor has been absorbed in 1 minute in this test, more preferably that at least 10% has been absorbed in 1 minute and most preferably at least 15% of the MAO-B inhibitor has been absorbed in 1 minute.
  • composition of the invention is formulated to promote absorption of the active ingredient through the buccal, sublingual, pharyngeal and/or oesophageal mucous membranes.
  • composition of the invention should be in a form which sustains the active ingredient in contact with the buccal, sublingual, pharyngeal and/or oesophageal mucous membranes .
  • the composition of the invention is in the form of a viscous emulsion, syrup or elixir, a sub-lingual tablet, a suckable or chewable tablet, softgel, lozenge, aqueous or non-aqueous drops or other dosage form designed to release the active ingredient in a controlled manner to saliva or to the buccal, pharyngeal and/or oesophageal mucous membranes, a fast- dispersing dosage form designed rapidly to release the active ingredient in the oral cavity, or a bioadherent system.
  • bioadherent system refers to a solid or liquid dosage form which, at body temperature, exhibits controlled release and bioadherence characteristics.
  • This type of dosage form may be an emulsion which is water in oil in nature and whose internal phase is greater than that of the external phase. Examples of such bioadherent systems may be found in U.S. Patent No. 5055303.
  • fast-dispersing dosage forms are particularly preferred since they will disintegrate rapidly in the mouth thereby safeguarding against potential abuse of selegiline and actual abuse of methylphenidate, amphetamine etc. Moreover, the ease of administration of such fast-dispersing dosage forms would be advantageous to school nurses, teachers, parents and children.
  • U.S. Patent No. 5120549 discloses a fast- dispersing matrix system which is prepared by first solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix- forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix.
  • U.S. Patent No. 5079018 discloses a fast- dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydratable gel or foam forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0°C or below to leave spaces in place of hydration liquid.
  • U.S. Patent No. 5298261 discloses fast-dispersing dosage forms which comprise a partially collapsed matrix network that has been vacuum-dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.
  • fast-dispersing dosage form therefore encompasses all the types of dosage -form described in the preceding paragraphs.
  • the fast-dispersing dosage form is of the type described in U.K. Patent No. 1548022, that is, a solid fast-dispersing dosage form comprising a network of the active ingredient and a water-soluble or water- dispersible carrier which is inert towards the active ingredient, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent.
  • composition of the invention disintegrates within 1 to 10 seconds, particulary 2 to 8 seconds, of being placed in the oral cavity.
  • the composition will preferably contain, in addition to the active ingredient, matrix forming agents and secondary components .
  • Matrix forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses ; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes .
  • matrix forming agents suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L- hydroxyproline, L-isoleucine, L-leucine and L- phenylalanine .
  • sugars such as mannitol, dextrose, lactose, galactose and trehalose
  • cyclic sugars such as cyclodextrin
  • inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates
  • amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-a
  • One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification.
  • the matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant.
  • the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution or suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved.
  • Suitable colouring agents include red, black and yellow iron oxides and FD & C dyes such as FD & C blue No. 2 and FD & C red No. 40 available from Ellis & Everard.
  • Suitable flavouring agents include mint, raspberry, liquorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavours and combinations of these.
  • Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.
  • Suitable sweeteners include asparta e, acesulfame K and thaumatin.
  • Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives .
  • Selegiline has already been mentioned above as an MAO-B inhibitor which can be used in the treatment of ADHD and narcolepsy according to the present invention.
  • Para-fluoroselegiline is an analogue of selegiline which is also a monoamine oxidase B inhibitor and exhibits very similar pharmacological activity to that of selegiline.
  • MAO-B inhibitors may be mentioned: lazabemide [N- (2-aminoethyl) -5-chloropyridine- 2-carboxamide hydrochloride]; rasagiline [2 , 3-dihydro-N- 2-propynyl-lH-inden-l-amine] ; 2-BUMP [N- (2 -butyl) -N- methylpropargylamine; M-2-PP [N-methyl-N- (2-pentyl) - propargylamine] ; MDL-72145 [beta- (fluoromethylene) -3 , 4- dimethoxy-benzeneethanamine] ; and mofegiline [(E) -4- fluoro- ⁇ - (fluoromethylene)
  • compositions in accordance with this invention include as the active MAO-B inhibitor a compound of the general formula :
  • X represents a hydrogen atom or, preferably, a methyl group and Y represents a fluorine or, preferably, a hydrogen atom. It is particularly preferred that X is methyl and Y is hydrogen i.e. that the active MAO-B inhibitor is selegiline .
  • Selegiline or para-fluoroselegiline which is absorbed by pre-gastric absorption from a composition in accordance with this invention passes straight into the systemic circulatory system thereby avoiding first pass metabolism in the liver. Accordingly, the initial rapid production of unwanted metabolites is reduced and the bioavailability of active selegiline or para-fluoroselegiline is increased.
  • the increased bioavailability of active selegiline or para-fluoroselegiline means that the dose of selegiline or para-fluoroselegiline may be reduced whilst still producing the desired beneficial effect.
  • the active ingredient preferably is present in the composition in an amount of from 1 to 30%, more preferably 1 to 20%, by weight of the composition. It is also preferred that the active ingredient is present in the composition in an amount of from 0.25 to 20 mg, more preferably 0.5 to 10 mg and, most preferably, 1.25 to 5 mg.
  • a method of treating Attention Deficit Hyperactivity Disorder and/or narcolepsy which comprises introducing into the oral cavity of a patient a therapuetically effective amount of a pharmaceutical composition as described above.
  • Example 1 The invention is further illustrated by the following examples.
  • Example 1 The invention is further illustrated by the following examples.
  • Gelatin (720g) and mannitol (540g) were dispersed in a portion of purified water (15.73kg) by mixing thoroughly in the bowl of a vacuum mixer. The remaining water (1.5 litres) was added under vacuum while mixing using an anchor stirrer. The mix was then heated to 40°C + 2°C and homogenised for ten minutes . The mix was cooled down to room temperature.
  • a 4500g portion of the mix was removed into a stainless steel vessel and glycine (360g) , aspartame (90g) , grapefruit flavour (54g) , Opatint yellow (54g) , citric acid (90g) and selegiline hydrochloride (360g) were then added sequentially to this portion while homogenising using a bench top homogeniser.
  • the remainder of the mix was transferred into a second stainless steel vessel.
  • the mix was homogenised for ten minutes using a bench top mixer to dissolve the drug.
  • the homogenised portion of the mix in the first vessel was returned to the mixer bowl together with the mix from the second vessel .
  • the combined mixes were then mixed for at least 20 minutes.
  • the bulk dispersion was then homogenised to ensure that mixing was complete.
  • Each blister was then coded with a batch number and over- wrapped in a preformed sachet by placing the blister in the sachet and sealing the open end of the sachet completely.
  • Each sachet was then labelled with the product name, batch number, date of manufacture and suppliers name.
  • Each unit dosage form had the following composition:
  • the aim of this experiment was to compare the bioavailability of the selegiline hydrochloride formulation of Example 1 with the commercially available tablet formulation of selegiline hydrochloride sold under the registered Trade Mark "Movergan” by Asta Medica AG, Weism ⁇ llerstrasse 45, 6000 Frankfurt am Main, Germany.
  • An open label, randomised, 2 -way crossover, volunteer study was performed as follows. Twenty four subjects of either sex, aged between 45 and 71 years, giving written informed consent underwent a thorough medical examination to establish their fitness to participate in the study. Subjects received study treatment in the order dictated by a pre-determined randomisation schedule. Subjects were given either the formulation of Example 1 or the "Movergan" formulation. Blood samples for determination of pharmacokinetic parameters were taken at baseline (immediately before drug administration), then after 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72 and 96 hours. The study procedures were repeated two weeks later, when subjects were crossed-over to receive their second drug administration. Selegiline hydrochloride was administered as single lOmg doses (made up from 2 x 5 mg tablets) of the formulation of Example 1 or of the "Movergan" formulation.
  • Assays were performed to determine the concentrations of selegiline, N-desmethylselegiline, methamphetamine and amphetamine in each of the blood plasma samples.
  • the following pharmacokinetic parameters were determined for all four analysed substances: bioavailability (as measured as the area under the curve (AUC) of the drug concentrations/time plot) , Cmax (the maximum plasma concentration achieved and Tmax (the time- point at which Cmax was observed) .
  • each figure is a plot of the concentration of a specific compound in a blood plasma sample versus the time at which the sample was taken for the formulation of Example 1 (Example 1) and the tablet formulation sold under the registered Trade Mark "Movergan” (Movergan) .
  • the specific compound is selegiline.
  • the specific compound is N-desmethylselegiline.
  • the specific compound is methamphetamine.
  • the specific compound is amphetamine.
  • the ratio of the area under the plasma concentration-time curve (AUC) for selegiline and the AUC for N-desmethylselegiline was 0.0233 for the "Movergan" formulation, indicating clearly the extensive metabolism of selegiline when administered in an existing dosage form.
  • the corresponding AUC ratio for Example 1 in Table 1 was 0.1894. This demonstrates that pre- gastric absorption of selegiline results in a greater proportion of the administered dose being absorbed in the unmetabolised form. It demonstrates further that the selegiline :N-desmethylselegiline AUC ratio can be used as another indicator of the degree of pre-gastric absorption in selegiline-containing compositions in accordance with this invention. It is generally preferred that the ratio of the selegiline AUC to the N-desmethylselegiline AUC should be greater than 0.05, more preferably greater than 0.075 and most preferably greater than 0.10.
  • the aim of this study was to assess the sublingual absorption of selegiline hydrochloride formulations produced according to Example 1.
  • the study was designed to compare the urinary excretion over 24 hours of phenylethylamine and 5-hydroxyindoleacetic acid (5-HIAA) from the subjects to whom such formulations had been administered.
  • Example 3 2 x 5mg selegiline tablets produced according to Example 1 kept in the mouth for 1 minute and then swallowed (Example 1 (lOmg) ) .
  • Blood samples for determination of pharmacokinetic parameters were taken at baseline (immediately before drug administration) and then after 0.08, 0.16, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 12 hours .
  • Urine samples were taken immediately before drug administration and during the periods 0-2 hours, 2-4 hours, 4-6 hours, 6-12 hours and 12-24 hours.
  • Assays were performed to determine the concentration of selegiline in each of the blood plasma and urine samples and the concentration of phenylethylamine and 5-hydroxyindoleacetic acid (5HIAA) was measured in each of the urine samples. Selegiline was also measured in saliva and mouth washings.
  • Phenylethylamine is the preferred substrate for monoamine oxidase B (MAO-B) and consequently its excretion has been shown to rise when MAO-B is inhibited.
  • 5HIAA is a breakdown product formed by the action of MAO- A on 5-hydroxytryptamine (serotonin) . When MAO-A is inhibited, the 5HIAA level excreted has been shown to decline .
  • Figure 5 is a plot of concentration of selegiline in a blood plasma sample versus the time at which the sample was taken for both expectorated and swallowed formulations produced according to Example 1 (Example 1 (equivalent to 2.96mg) and Example 1 (lOmg) respectively) and the lOmg tablet formulation sold under the registered Trade Mark "Eldepryl”.
  • Figure 6 shows the cumulative 5-hydroxyindoleacetic acid excretion in urine over 24 hours.
  • Figure 7 shows the cumulative phenylethylamine excretion in urine over 24 hours.
  • Example 1 Lack of inhibition of monoamine oxidase A by the Example 1 (lOmg "swallowed") and Example 1 (2.96mg “expectorated”) treatments was confirmed by analysis of the urine samples for concentration of 5- hydroxyindoleacetic acid, which is the metabolite of 5- hydroxytryptamine (serotonin) which is a principal substrate for monoamine oxidase A (see Figure 6) .
  • Urinary concentrations of 5-hydroxyindoleacetic acid were similar for the Example 1 (lOmg "swallowed"), Example 1 (2.96mg “expectorated”) and the standard "Eldepryl” tablet formulations, showing that the selegiline formulations produced according to Example 1 did not cause greater MAO-A inhibition than standard tablets despite the much increased selegiline bioavailability.
  • the aim of this experiment was to determine and compare the bioavailability of selegiline from a single tablet of the selegiline hydrochloride formulation of Example 1 with that from two tablets of the commercially available UK tablet formulation sold under the registered trade mark "Eldepryl” by Britannia Pharmaceuticals Ltd. of 41-75 Brighton Road, Redhill, Surrey RH1 6YS .
  • An open label randomised, 2 -way crossover, volunteer study was performed as follows . Twelve healthy volunteers of either sex, aged between 40 and 75 years, giving written informed consent underwent a thorough medical examination to establish their fitness to participate in the study. Subjects received each study treatment in an order dictated by a pre-determined randomisation schedule. Subjects were given either one tablet of the formulation of Example 1 (5mg selegiline hydrochloride) or two tablets of the "Eldepryl" formulation (lOmg selegiline hydrochloride) after an overnight fast .
  • Blood samples for determination of pharmacokinetic parameters were taken at baseline (immediately before drug administration) , and then after 5, 10, 15, 30, 45, 60 minutes and 1.5, 2, 3, 4, 6, 22 and 24 hours post-dose) .
  • Urine samples were collected in 6 hourly aliquots for 24 hours prior to and 24 hours after each selegiline dose. The study procedures were repeated three weeks later, when subjects were crossed over to receive their second drug administration.
  • Assays were performed to determine the concentration of selegiline in each of the blood plasma samples and the concentration of phenylethylamine (PEA) in each of the urine samples .
  • Figure 8 is a plot of concentration of selegiline in a blood plasma sample versus the time at which the sample was taken for the formulation of Example 1 (Example 1) and the tablet formulation sold under the registered Trade Mark “Eldepryl” (Eldepryl) and Figure 9 shows the cumulative phenylethylamine excretion in urine over 24 hours prior to and after each selegiline dose.

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Abstract

La présente invention se rapporte à l'utilisation d'une composition pharmaceutique administrée oralement renfermant un vecteur, tel qu'un ingrédient actif et un inhibiteur de B oxydase monoamine. L'invention est caractérisée en ce que la composition est formulée pour faciliter l'absorption pré-gastrique dudit inhibiteur de B oxydase monoamine et la fabrication d'un médicament pour traiter l'hyperactivité avec déficit de l'attention et/ou la narcolepsie. Par ailleurs, l'invention concerne une méthode de traitement de l'hyperactivité avec déficit de l'attention et/ou la narcolepsie.
PCT/GB1998/002124 1997-07-17 1998-07-17 Traitement de l'hyperactivite avec deficit de l'attention et de la narcolepsie WO1999003458A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP98967116A EP1028719A1 (fr) 1997-07-17 1998-07-17 Traitement de l'hyperactivite induite par les troubles d'attention et de la narcolepsie
AU16456/99A AU1645699A (en) 1997-07-17 1998-07-17 Treatment of attention deficit hyperactivity disorder and narcolepsy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9715082.5 1997-07-17
GB9715082A GB9715082D0 (en) 1997-07-17 1997-07-17 Treatment of attention deficit hyperactivity disorder and narcolepsy

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WO1999003458A1 true WO1999003458A1 (fr) 1999-01-28

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA016843B1 (ru) * 2006-12-14 2012-07-30 Тева Фармасьютикал Индастриз, Лтд. Таннат разагилина
US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin
US12312375B2 (en) 2017-10-09 2025-05-27 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use

Citations (10)

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EP0241809A1 (fr) * 1986-04-16 1987-10-21 ASTA Pharma Aktiengesellschaft Association synergétique d'amantadine et de sélégiline
EP0436492A2 (fr) * 1990-01-03 1991-07-10 Teva Pharmaceutical Industries Limited R-Enantiomère de N-propargyl-1-aminoindane, son préparation et composition pharmaceutique le contenant
WO1992015551A1 (fr) * 1991-03-01 1992-09-17 University Of Saskatchewan Propargylamines aliphatiques utilisees en tant qu'inhibiteurs selectifs de mao-b et agents neuroprotecteurs
EP0538134A2 (fr) * 1991-10-16 1993-04-21 Teva Pharmaceutical Industries, Ltd. Dérivés mono-fluorés de N-propargyl-1-aminoindane et leur usage comme inhibiteurs de monoamine oxidase
WO1994027588A1 (fr) * 1993-05-20 1994-12-08 Sabelli Hector C Procedes et compositions servant a traiter la depression et d'autres maladies psychiatriques
WO1995011016A1 (fr) * 1993-10-18 1995-04-27 Teva Pharmaceutical Industries Ltd. R-enantiomere de n-propargyl-1-amino-indane, sels, compositions et utilisation de ce compose
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