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WO2003017984A1 - Forme posologique orale a liberation prolongee - Google Patents

Forme posologique orale a liberation prolongee Download PDF

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Publication number
WO2003017984A1
WO2003017984A1 PCT/SE2002/001542 SE0201542W WO03017984A1 WO 2003017984 A1 WO2003017984 A1 WO 2003017984A1 SE 0201542 W SE0201542 W SE 0201542W WO 03017984 A1 WO03017984 A1 WO 03017984A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
extended release
oral dosage
release oral
active substance
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.)
Ceased
Application number
PCT/SE2002/001542
Other languages
English (en)
Inventor
Karin Ellström
Ulf Kjellberg
Håkan NYQVIST
Anders Ringberg
Annika Schweighofer
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.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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 AstraZeneca AB filed Critical AstraZeneca AB
Publication of WO2003017984A1 publication Critical patent/WO2003017984A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to a new extended release oral dosage form of a good soluble pharmaceutically active substance, (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H- l-benzopyran-5-carboxamide, in the form of the free base or pharmaceutically acceptable salts and/or hydrates or solvates thereof, for use in the prevention and/or treatment of central nervous system (C ⁇ S) disorders and related medical disturbances, especially 5- hydroxytryptamine mediated disorders and disturbances.
  • C ⁇ S central nervous system
  • the invention relates to an extended release oral dosage form that provides a defined blood concentration profile having no rapid initial rise in blood plasma concentration of the good soluble active substance when administered at low dose.
  • the invention further relates to processes for preparing said dosage form, the use of said dosage form for the manufacture of a medicament and a method of prevention and/or treatment of C ⁇ S disorders and related medical disturbances using said dosage form.
  • Extended release dosage forms can be used to overcome these problems.
  • An extended release oral dosage form makes it possible to deliver an active substance to the blood in a controlled way such that the initial sha ⁇ rise in blood plasma concentration of the active substance is avoided.
  • Another advantage of extended release oral dosage forms is the possibility to administer the prescribed daily dose of the active substance in the form of one unit dose while maintaining the desired therapeutic response over a period of up to 24 hours. In this way, the administration will be more user-friendly. Furthermore, the risk for therapeutic inefficiency due to bad compliance to frequent dosing and the lack of dosing during the night can be minimised.
  • Extended release oral dosage forms further have the potential for improving treatment of e.g. chronic diseases. Besides, both systemic and local side effects, e.g. gastrointestinal irritation due to high local concentrations of the active substance, can be reduced.
  • the present invention provides for an extended release dosage form which is especially suitable for a good soluble active substance comprising a homogeneous mixture of the good soluble active substance, a gel-forming polymer and optionally other excipients, whereby the amount of the active substance is preferably low in the dosage form ( ⁇ 10% w/w).
  • the dosage form may be coated or uncoated.
  • the oral dosage form of the present invention provides for a defined release profile of the active substance in vivo over a predetermined period of up to 24 hours, whereby also the rapid initial rise in blood plasma concentration of the active substance is avoided.
  • the extended release oral dosage form according to the present invention provides a blood concentration profile of the active substance having a slower rise in peak plasma concentration compared to a conventional immediate release dosage form, thereby avoiding the adverse effects related to high peak plasma concentrations.
  • Active substances for use in the present invention are good soluble pharmaceutically active substances for use in the prevention and/or treatment of disorders and related disturbances in the CNS.
  • the present invention is especially suitable for substances having a short half- life and/or a rapid initial rise in blood plasma concentration.
  • 5- hydroxytryptamine receptor agonists, partial agonists or antagonists preferably (R)-3-N,N- dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide in the form of the free base or pharmaceutically acceptable salts and/or hydrates or solvates thereof.
  • the salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran- 5-carboxamide hydrogen tartrate.
  • This tartrate comprises any of the optical forms (2R,3S), (2R,3R) and (2S,3S).
  • the blood plasma concentration 24 hours after administration (C 2 ) of an active substance, given in the extended release oral dosage form of the present invention, should be at least 25 % of the maximum blood plasma concentration (C max ), preferably at least 40%, when the dose is administered orally to healthy fasting volunteers, and at least 13 % of the maximum blood plasma concentration (C max ) when the administration of an active substance is combined with food intake (high fat standardised breakfast).
  • the values for C max and C 24 are average values from at least 11 volunteers.
  • the extended release oral dosage form according to the present invention provides a blood plasma concentration profile of the active substance having a slower rise in blood plasma concentration compared to a conventional immediate release dosage form, thereby avoiding the adverse effects related to high peak plasma concentrations.
  • the time to reach the maximum blood plasma concentration (t m ⁇ ) for an active substance, after being administered in the extended release oral dosage form of the present invention, should be at least five times as long as the t max obtained after oral administration of said substance in an aqueous solution.
  • the values have been calculated as the average values obtained from at least 35 volunteers.
  • Other parameters that can be used to. express the blood plasma concentration profile of an active substance provided for by the extended release oral dosage form of the present invention are the area under the curve (AU nf ), the mean residence time (MRT lnf ) and the relative bioavailability (F re ⁇ ).
  • the MRT; nf of an active substance reflects the mean time a molecule resides in the body.
  • the MRTi nf of the extended release oral dosage form of the present invention should be at least three times as long as the MRTj nf of the same substance when administered orally in an aqueous solution to fasting volunteers.
  • the MRT ⁇ n f is preferably between 5 and 15 hours, most preferably between 10 and 14 hours.
  • An aqueous solution shall mean a water solution containing the active substance.
  • the present invention relates to an extended release oral dosage form that provides a release profile of the active substance that is rather unaffected by food intake.
  • the influence of food intake should be such that the ratio of AU nf , MRT M and F re ⁇ between food intake and non-food intake is between 0.8 to 1.3, preferable between 0.8 and 1.1.
  • the present invention relates to an extended release oral dosage form, which provides therapeutic levels of the active substance in blood plasma for at least 24 hours, and which has an in vitro dissolution profile in a phosphate buffer, pH 6.8, using USP Paddle method at 50 ⁇ m, such that about 30 to 45 % of the active substance is released after 5 hours, about 60 to 75 % is released after 10 hours and about 85 to 100 % is released after 24 hours.
  • the dosage form of the invention shall contain at least one gel-forming polymer, which may be selected from the group of hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, polyethylene glycols, polyethylene oxide and poloxamers.
  • the gel-forming polymer is hydroxypropyl methylcellulose (HPMC).
  • HPMC hydroxypropyl methylcellulose
  • the viscosity of the HPMC should be between 3000 and 21000 cP, preferably 7500 and 21000 cP, and most preferably 11250 and 21000 cP of a 2% (w/w) aqueous solution at 20°C.
  • the substitution degree of methoxy groups of this cellulose should be from 19 to 30 % by weight, preferably from 19 to 28 % and most preferably from 19 to 24 % by weight and the substitution degree of hydroxypropoxy groups should be from 4 to 12 % by weight, most preferably 7 to 12 % by weight.
  • This HPMC may be mixed with a low viscosity HPMC.
  • the low viscosity cellulose should have a viscosity within 3.75 and 140 cP, preferably from 11.3 to 140 cP and most preferably from 37.5 to 70 cP of a 2% (w/w) aqueous solution at 20°C.
  • the substitution degree of methoxy groups of this cellulose should be from 19 to 30 % by weight, preferably from 19 to 28 % and most preferably from 19 to 24 % by weight.
  • the substitution degree of hydroxypropoxy groups should be from 4 to 12 % by weight, most preferably 7 to 12 % by weight.
  • the ratio of active substance to gel-forming polymer in the extended release oral dosage form of the present invention may be from 1: 10 to 1:70, preferably from 1:20 to 1:50.
  • the dosage form may optionally comprise excipients, e.g. binders, release modifying agents, lubricants, flow condition agents and the like.
  • Suitable binders are hydroxypropyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, gelatine, polyethylene glycol, glycerylbehenate, glycerylmonostearate, carnauba wax and the like.
  • the preferred binder is microcrystalline cellulose and/or polyvinylpyrrolidone.
  • the amount of binder in the composition is from 0 to 45 % w/w.
  • the ratio of active substance to binder may be from 1:1 to 1:10, preferably from 1:2 to 1:6.
  • excipients that may be used in the dosage form are lubricants, such as magnesium stearate, sodium stearyl fumarate, stearic acid, polyethylene glycol, talc and the like, flow condition agents, such as colloidal silicon dioxide, talc and the like.
  • lubricants such as magnesium stearate, sodium stearyl fumarate, stearic acid, polyethylene glycol, talc and the like
  • flow condition agents such as colloidal silicon dioxide, talc and the like.
  • lactose lactose, mannitol, sorbitol, calcium phosphate, aluminium silicate, paraffin, carboxypolymethylene, carboxyvinyl polymer, acrylic acid polymer, ethyl cellulose, polyethylene glycol and the like.
  • excipients such as taste agents and colouring agents may be used. The amounts of these excipients are 0 to 55 % w/w.
  • the dosage form may be prepared by mixing the active substance, the gel-forming polymers and optionally other excipients such as binders, lubricants and the like in a suitable mixer, e.g. a Turbula mixer, followed by direct compression of said homogeneous mixture.
  • a suitable mixer e.g. a Turbula mixer
  • the dosage form may be prepared from a granulated powder.
  • the homogeneous powder may be obtained by mixing the active substance, the gel-forming polymers and optionally excipients such as binders in a suitable mixer. Then the mixture may be granulated in a mixer.
  • the granulation can be performed in water or another granulation liquid such as an alcohol, e.g. ethanol, methanol, isopropanol, a ketone, e.g. acetone or aqueous mixtures thereof. From an environmental point of view water is preferred.
  • the combination of PVP and HPMC in the ratio of 1 to 3, as used in one of the embodiments of the present invention, makes it feasible to use water as the granulation liquid instead of an organic liquid.
  • the resultant wet granulation may thereafter be dried in a drying cabinet or in a fluid bed dryer and milled through a screen.
  • the granulation may also be performed at elevated temperatures by using meltable binders.
  • the cooled granulation may be milled through a screen.
  • the dry granulate powder mass is then mixed with the remaining excipients and compressed into a suitable dosage form.
  • the dosage form may be prepared by first compressing the dry granulate powder mass into loose compacts. These loose compacts may be milled through a screen and finally mixed with other excipients such as binders, lubricants and flow condition agents.
  • the dry, homogeneous powder mass may then be manufactured into a suitable dosage form, e.g. compressed into tablets in a tablet machine.
  • Other suitable oral dosage forms are capsules, minitablets and the like.
  • the dosage form may comprise a coating layer.
  • This coating layer may optionally have an extended release function and could contain additives for the modification of the release of the pharmaceutically active substance.
  • Suitable polymers that can be used in the coating layer are ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, acrylic and methacrylic esters such as Eudragit RL and RS (Rohm Pharma). Ethyl acrylate and methyl methacrylate such as Eudragit NE (Rohm Pharma) may also be used in the coating layer.
  • the coating layer may further comprise binders such as microcrystalline cellulose, hydroxypropyl cellulose and the like, plastizicers such as polyethylene glycol, acetyl tributyl citrate and the like and colour agents such as titanium dioxide, iron oxide and the like. Also, antiadhesion agents such as colloid silicon dioxide, talc and the like may be used in the coating layer.
  • the coating layer may additionally comprise taste-masking agents.
  • coating fluid may be used water or alcohols such as ethanol, optionally containing antibacterial agents such as hydrogen peroxide.
  • the coating layer may be applied by way of spray coating in a fluidised bed, pan-coating or another coating technique known to a person skilled in the art.
  • the extended release dosage form of the present invention is preferably coated.
  • composition from which the dosage form is prepared can be formulated to contain the active substance in different amounts, e.g. between 0.1 and 100 mg, preferably between 0.5 and 50 mg, more preferably between 1 and 25 mg, particular preferred between 2.5 and 10 mg, but is not limited to these intervals.
  • Suitable daily doses of the active substance may vary within a wide range and will depend on various factors such as the relevant disorder or medical conditions, the age, weight and sex, and may be determined by a physician.
  • the extended release oral dosage form according to the invention may be used in the prevention and/or treatment of CNS disorders and related medical disturbances, urinary incontinence, vasospasm or growth control of tumours, particularly, for 5- hydroxytryptamine mediated disorders and medical disturbances.
  • the extended release oral dosage form could for example be used in the prevention and/or treatment of affective disorders mood disorders e.g. depression, major depressive episodes, dysthymia, seasonal affective disorder, depressive phases of bipolar disorder, anxiety disorders e.g. obsessive compulsive disorder, panic disorder with/without agoraphobia, social phobia, specific phobia, generalised anxiety disorder, posttraumatic stress disorder, personality disorders e.g.
  • disorders of impulse control trichotellomania, sleep disorders, eating disorders e.g. obesity, anorexia, bulimia, pre-menstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders e.g. age associated memory impairment, presenile and senile dementia such as Alzheimer's disease, pathological aggression, schizophrenia, endocrine disorders e.g. hype ⁇ rolactinaemia, stroke, dyskinesia, Parkinson's disease, thermoregulation, pain, hypertension, urinary incontinence such as over active bladder, detrusor instability, neurogenic bladder, detrusor hyperreflexia, nocturnal enuresis, e.g.
  • the present invention also relates to processes for the manufacture of the extended release oral dosage form characterized by,
  • Method A comprising the steps:
  • Method B comprising the steps:
  • Method C comprising the steps:
  • Cii) granulating said mixture is Ciii) optionally drying the obtained granulate,
  • the term 'extended release oral dosage form' shall mean any oral dosage form, which continuously releases the active substance at rates, which are sufficient to provide periods of prolonged therapeutic action following each administration of a single dose of such a dosage form.
  • Alternative naming is e.g. controlled, sustained and slow release.
  • 25 According to the Biopharmaceutical Classification System used by the FDA, the term 'good soluble' shall means, the maximum dose to be administered, should be able to dissolve in 250 ml of an aqueous solution in the pH range of 1 to 8.
  • the aqueous solution is preferably water.
  • HPC Hydroxypropylcellulose (molecular weight approx. 95,000, pharmaceutical grade)
  • HPMC (15000 cP) has a viscosity within the range of 11250-21000 cP and a substitution degree of methoxy groups of 19-24 % by weight and hydroxypropoxy groups of 7-12 % by weight.
  • the viscosity values are given for 2 % (w/w) aqueous solutions at 20°C.
  • the active substance, (R) -3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l- benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate, ⁇ PMC (15000 cP) and polyvinylpyrrolidone were sieved through a 0.5 mm screen (or 1.0 mm screen for ⁇ PMC and PVP) and were mixed in a Turbula mixer for 10 minutes at a speed of 33 rpm.
  • the powder mixture was granulated with water in an intensive mixer during water addition and additionally mixed for 2 minutes.
  • the wet granulation was dried in a drying cabinet at 45°C for 10 hours.
  • the granulation was milled through a screen of 1.25 mm in an oscillating mill at 147 ⁇ m.
  • the granulation was compacted into loose compacts in a tablet machine equipped with punches of 0 11 mm.
  • the compacts were milled through a screen of 4 mm and then through a screen of 1.25 mm.
  • the milled granulation was mixed with microcrystalline cellulose and colloidal silicon dioxide (screened through 0.5 mm) in a Turbula mixer for 6 minutes at a speed of 33 ⁇ m.
  • Sodium stearyl fumarate was added through a 0.5 mm screen and the mixing was continued for further 2 minutes.
  • the final homogeneous powder mixture was compressed into tablets in a tablet machine equipped with normally curved punches of 0 10 mm.
  • the tablets were spray-coated in a tablet coating machine using an aqueous coating suspension of ⁇ PMC (6 cP) and PEG6000 and high speed homogenised suspended titanium dioxide,
  • Example 2 Ethanol 95 vol% 179 In Example 2 the tablets were compressed using normally curved punches of 0 8 mm. Otherwise the tablets were produced in the same manner as in Example 1.
  • Example 3 The following components expressed as mg per tablet were used; batch size 5800 tablets:
  • Eudragit® RS30D 4.9 Eudragit® RL30D 1.6 ATBC 2.1
  • Example 3 the tablets were finally compressed using normally curved punches of 0 8 mm.
  • the coating suspension was prepared by stirring Eudragit RS30D, Eudragit RL30D, ATBC and part of the water for 19 hours. Colloidal silicon dioxide, talc, titanium dioxide and part of the water were high speed mixed separately and then poured into the 19 hours stirred suspension.
  • the coating layered tablets were coalesced in a drying cabinet at 45°C ⁇ for 15 hours. Otherwise the tablets were produced in the same manner-as in Example 1.
  • (2i?,3i?)-tartrate monohydrate were tested. 11 to 12 volunteers tested each formulation.
  • the extended release formulations were given in the fasting state and together with a high fat breakfast.
  • the extended release oral dosage forms given were manufactured according to Examples 1-3 of the present invention.
  • An aqueous solution was given as a reference formulation.
  • the results show that the extended release oral dosage form according to the present invention provides for a defined plasma concentration of the good soluble active substance over a period of at least 24 hours.
  • the blood plasma concentration after 24 hours (C 24 ) is at least 25% of the maximum blood plasma concentration (C max ) in the fasting state, preferably at least 40% and at least 13% of C max when administered together with food.
  • the results also show that the MRTj nf increases at least three times when the active substance is administered in the extended release oral dosage form of the present invention compared to when administered orally in an aqueous solution to fasting volunteers. Beside, the results show that the effect of food intake is minimized after administration of the good soluble active substance in the extended release oral dosage form according to the present invention.
  • the blood plasma profile of the active substance is affected by food intake such that the ratio of AU nf , MRTi nf and F re ⁇ between food and no food intake is between 0.8 to 1.3, preferably between 0.8 and 1.1.
  • the extended release oral dosage form according to the present invention provides a blood plasma profile of the good soluble active substance with a prolonged time of the maximum peak concentration (t ma ⁇ )-
  • t ma ⁇ the time to reach maximum concentration
  • Figure 1 The average blood plasma concentrations obtained as average values obtained from 35 volunteers after administration of an active substance, (R) -3-NN- dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate, in either an aqueous solution (2.5 mg) or in the extended release oral dosage forms according to the present invention with or without simultaneous food intake.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une forme posologique orale à libération prolongée d'une substance pharmaceutiquement active et à bonne solubilité. (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide, se présentant sous la forme d'une base libre, ou leurs sels pharmaceutiquement tolérables et/ou leurs hydrates ou solvates destinés à être utilisés dans la prévention et/ou le traitement de troubles du système nerveux central et des perturbations médicales associées. L'invention concerne plus particulièrement une forme posologique orale à libération prolongée qui donne un profil de concentration sanguine dépourvu d'augmentation initiale rapide de la concentration du plasma sanguin de la substance active à bonne solubilité lorsqu'elle est administrée à faible dose. L'invention concerne enfin des procédés de préparation de cette forme posologique, son utilisation et un procédé de prévention et/ou de traitement de troubles du système nerveux central et des perturbations médicales associées à l'aide de cette forme posologique.
PCT/SE2002/001542 2001-08-29 2002-08-28 Forme posologique orale a liberation prolongee Ceased WO2003017984A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0102888-5 2001-08-29
SE0102888A SE0102888D0 (sv) 2001-08-29 2001-08-29 New formulation

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WO2003017984A1 true WO2003017984A1 (fr) 2003-03-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1523981A1 (fr) * 2003-10-13 2005-04-20 Wyeth Préparations à libération prolongée de la venlafaxine
WO2007136737A1 (fr) * 2006-05-19 2007-11-29 Adamas Pharmaceuticals, Inc. Procédés et compositions destinés au traitement d'infections virales

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0148811A1 (fr) * 1984-01-10 1985-07-17 Lejus Medical Aktiebolag Composition pharmaceutique
EP0231826A2 (fr) * 1986-02-04 1987-08-12 Farvalsa AG Comprimé de théophylline à libération retardée
GB2195893A (en) * 1986-10-09 1988-04-20 Sandoz Ltd Sustained release composition
EP0797991A1 (fr) * 1996-03-25 1997-10-01 American Home Products Corporation Compositions de venlafaxine à libération prolongée
WO1998054166A1 (fr) * 1997-05-30 1998-12-03 Astra Aktiebolag Nouveau sel
WO2001091750A1 (fr) * 2000-05-26 2001-12-06 Pharmacia Corporation Utilisation d'une composition de celecoxibe pour soulagement rapide de la douleur

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0148811A1 (fr) * 1984-01-10 1985-07-17 Lejus Medical Aktiebolag Composition pharmaceutique
EP0231826A2 (fr) * 1986-02-04 1987-08-12 Farvalsa AG Comprimé de théophylline à libération retardée
GB2195893A (en) * 1986-10-09 1988-04-20 Sandoz Ltd Sustained release composition
EP0797991A1 (fr) * 1996-03-25 1997-10-01 American Home Products Corporation Compositions de venlafaxine à libération prolongée
WO1998054166A1 (fr) * 1997-05-30 1998-12-03 Astra Aktiebolag Nouveau sel
WO2001091750A1 (fr) * 2000-05-26 2001-12-06 Pharmacia Corporation Utilisation d'une composition de celecoxibe pour soulagement rapide de la douleur

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1523981A1 (fr) * 2003-10-13 2005-04-20 Wyeth Préparations à libération prolongée de la venlafaxine
WO2005039555A1 (fr) * 2003-10-13 2005-05-06 Wyeth Preparations de venlafaxine pour comprimes a liberation prolongee
WO2007136737A1 (fr) * 2006-05-19 2007-11-29 Adamas Pharmaceuticals, Inc. Procédés et compositions destinés au traitement d'infections virales

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