WO2019097120A1 - Nouvelle utilisation et nouvelles formes posologiques pharmaceutiques - Google Patents

Nouvelle utilisation et nouvelles formes posologiques pharmaceutiques Download PDF

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Publication number
WO2019097120A1
WO2019097120A1 PCT/FI2018/050834 FI2018050834W WO2019097120A1 WO 2019097120 A1 WO2019097120 A1 WO 2019097120A1 FI 2018050834 W FI2018050834 W FI 2018050834W WO 2019097120 A1 WO2019097120 A1 WO 2019097120A1
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WIPO (PCT)
Prior art keywords
isophthalonitrile
methylbenzyl
dihydroxy
levodopa
dosage form
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PCT/FI2018/050834
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English (en)
Inventor
Frederic Dargelas
Juha Ellmen
Satu LAKIO
Heidi LEPPINEN
Toni SARAPOHJA
Elina TURUNEN
Mikko Vahteristo
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Orion Corporation
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Publication of WO2019097120A1 publication Critical patent/WO2019097120A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present disclosure relates to 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile, carbidopa and levodopa for use in a method for the treatment of Parkinson's disease as well as to pharmaceutical dosage forms used in said method.
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile is a catechol O-methyltransferase (COMT) inhibitor disclosed in WO 2013/175053.
  • COMP catechol O-methyltransferase
  • Levodopa ((-)-L-alpha-amino-beta-(3,4-dihydroxybenzene)propanoic acid) is a commonly used drug in the treatment of Parkinson's disease (PD). It is commercially available as a combination with an aromatic amino acid decarboxylase (AADC) inhibitor, such as carbidopa ((-)-L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxybenzene)propionic acid
  • AADC aromatic amino acid decarboxylase
  • Sinemet® and the combination of levodopa, carbidopa and the COMT inhibitor entacapone under the trademark Stalevo®.
  • PD patients frequently experience motor complications, including wearing off symptoms, such as "end-of-dose wearing off' symptoms, "early morning dystonia” and “on/off fluctuations", and dyskinesia.
  • wearing off symptoms such as "end-of-dose wearing off' symptoms, "early morning dystonia” and “on/off fluctuations", and dyskinesia.
  • end-of-dose wearing off the effect of a dose of a PD drug decreases (wears off), the drug concentration decreases in plasma and subsequently in the brain, and the severity of PD symptoms, e.g., bradykinesia, rigidity, and resting tremor, are increased before the next dose is taken.
  • a PD patient with "end-of-dose wearing off' or "on/off fluctuations” may experience poor gastrointestinal tract mobility and swallowing difficulties.
  • the wearing off symptoms may also include non-motor symptoms, such as anxiety and pain.
  • non-motor symptoms such as anxiety and pain.
  • the reasons for the fluctuation episodes are not completely understood but may be, in part, related to oscillating plasma levels of levodopa in turn leading to intermittent or pulsatile stimulation of striatial dopamine receptors in the brain.
  • End-of-dose wearing off symptoms or on/off fluctuations comprise alternations between periods of relatively good mobility ("on" periods) and periods of relatively impaired motor function ("off periods) often associated with simultaneous non motor symptoms.
  • Dyskinesia are involuntary movements in the body of a PD patient often associated with high maximum or peak concentrations (C max ) of a PD drug, such as levodopa.
  • the present disclosure provides 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile, carbidopa and levodopa for use in a method for the treatment of Parkinson's disease by a simultaneous or sequential administration to a patient of
  • the present disclosure also provides an oral dosage form comprising
  • Figure 1 X-ray powder diffractogram of crystalline form II of 4,5-dihydroxy-2-(4- methylbenzyl)isophthalonitrile monohydrate obtained in Example 18.
  • the inventors have surprisingly found that the COMT inhibitor 4,5-dihydroxy-2-(4- methylbenzyl)isophthalonitrile, when administered in combination with a carbidopa dose from 65 to 105 mg, dose dependently significantly increases the AUC 0-24h and also the minimum concentrations of levodopa without significantly increasing its maximum
  • the treatment according to the invention when compared to Sinemet® IR (100 mg levodopa, 25 mg carbidopa), doubles the levodopa AUC 0-24h and almost triples without significantly increasing Thus, the treatment decreased levodopa
  • the present disclosure provides 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile, carbidopa and levodopa for use in a method for the treatment of Parkinson's disease by a simultaneous or sequential administration to a patient of
  • the present disclosure provides a method for the treatment of Parkinson's disease by a simultaneous or sequential administration to a patient in need of treatment of Parkinson's disease of
  • levodopa in an amount ranging from 50 to 200 mg.
  • the present disclosure provides the use of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile, carbidopa and levodopa in a method for the manufacture of a medicament for the treatment of Parkinson's disease by a simultaneous or sequential administration to a patient of
  • the present disclosure also provides an oral dosage form comprising
  • an oral dosage form comprising
  • the PD patient to be treated is a high catechol O- methyltransferase activity (COMT HH ) or an intermediate activity (COMT HL ) patient.
  • COMP HH catechol O- methyltransferase activity
  • COMP HL intermediate activity
  • the patient is a wearing off patient.
  • the three active ingredients are administered to the PD patient in a repeated manner.
  • carbidopa is present in an amount of 65 mg.
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile is present in an amount of 100 mg.
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile is crystalline form II of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile monohydrate having at least peaks at 20 of about 6.1° and 11.2° in an X-ray powder diffractogram.
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile is crystalline form II of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile monohydrate having at least peaks at 20 of about 6.1° and 14.7° in an X-ray powder diffractogram.
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile is crystalline form II of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile monohydrate having at least peaks at 20 of about 6.1°, 11.2°, 14.7°, 16.2°, 21.8°, 24.0°, 26.2° and 26.9° in an X- ray powder diffractogram.
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile is crystalline form II of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile monohydrate characterized by an X-ray powder diffractogram substantially as illustrated in Figure 1.
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile is crystalline form II of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile monohydrate containing less than 25 % by weight of other 4,5-dihydroxy-2-(4- methylbenzyl)isophthalonitrile solvates and crystalline forms thereof.
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile is crystalline form II of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile monohydrate containing less than 10 % by weight of other 4,5-dihydroxy-2-(4- methylbenzyl)isophthalonitrile solvates and crystalline forms thereof
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile is crystalline form II of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile monohydrate containing less than 6 % by weight of other 4,5-dihydroxy-2-(4- methylbenzyl)isophthalonitrile solvates and crystalline forms thereof
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile is crystalline form II of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile monohydrate containing less than 4 % by weight of other 4,5-dihydroxy-2-(4- methylbenzyl)isophthalonitrile solvates and crystalline forms thereof.
  • levodopa is present in an amount of 50 mg, 100 mg, 150 mg or 200 mg.
  • the treatment comprises administering an oral solid dosage form.
  • the oral dosage form is a combination dosage form.
  • the oral dosage form is a capsule
  • the oral dosage form is a tablet.
  • 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile and carbidopa are in the same granules.
  • the total drug load of 4,5-dihydroxy-2-(4- methylbenzyl)isophthalonitrile and carbidopa in the granules is from 60 to 95 w/w % or from 70 to 85 w/w % or from 80 to 85 w/w %.
  • levodopa is in a pellet.
  • the pellet is coated.
  • the pellet is uncoated.
  • levodopa is in a granule.
  • the drug load of levodopa in the pellet is from 60 to 90 w/w % or from 70 to 80 w/w % or from 70 to 75 w/w %.
  • a high drug load of granules and/or pellets is considered to be preferred, especially when the dosage form is a capsule as patients suffering from Parkinson ' s disease have often swallowing problems.
  • the dosage form is an immediate release dosage form with regard to 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile and carbidopa.
  • the dosage form is immediate release or slightly modified release dosage form with regard to levodopa.
  • diffractograms can be subject to variation of ⁇ 0.2° 20 depending on various factors, such as temperature, concentration and instrumentation used. Therefore, the position of peaks is referred to herein as being at“about” specific values.
  • Polymorphic purity can be assessed with a method known in the art. Suitable methods include, but are not limited to, gas chromatography, column chromatography, liquid chromatography, high-pressure liquid chromatography, thin layer chromatography, mass spectrometry and high-resolution mass spectrometry.
  • 4,5-Dihydroxy-2-(4-methylbenzyl)isophthalonitrile, carbidopa and levodopa when used in the context of this disclosure also include pharmaceutically acceptable salts, hydrates or prodrugs (including esters) thereof.
  • pharmaceutically acceptable salt refers to a salt of a compound that is
  • pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound include, but are not limited to, potassium and sodium salts.
  • esters refers to an ester of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound.
  • esters may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals.
  • Non-limiting examples of these esters include esters formed with aliphatic or aromatic alcohols.
  • Representative examples of pharmaceutically acceptable esters include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl, and benzyl esters.
  • prodrug refers to a derivative of a drug substance which releases said active parent drug substance in vivo when such prodrug is administered to a patient.
  • prodrug refers to a derivative of a drug substance which releases said active parent drug substance in vivo when such prodrug is administered to a patient.
  • treatment of Parkinson's disease refers to relieving and/or delaying the worsening of one or more of the symptoms and/or motor complications related to idiopathic Parkinson's disease, e.g. bradykinesia, rigidity, and resting tremor.
  • idiopathic Parkinson's disease e.g. bradykinesia, rigidity, and resting tremor.
  • simultaneous administration refers to administration of the disclosed drug substances at the same time in separate formulations or as a combination formulation, i.e. in a single dosage form.
  • sequential administration refers to administration of the disclosed drug substances one after the other, i.e. not at the same time, in two or more separate dosage forms, for example, 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile may be administered as a separate dosage form and levodopa and carbidopa may be administered in a combination formulation. If the disclosed drug substances are administered sequentially, then typically administration of the last drug substance is begun an hour or less, generally 30 minutes or less, after administration of the first drug substance is begun.
  • COMPUT HH patient is a PD patient with a homozygous polymorphic genotype having a high catechol O-methyltransferase enzyme activity.
  • COMPOST HL patient is a PD patient with a heterozygous polymorphic genotype having an intermediate catechol O-methyltransferase enzyme activity.
  • COMP LL patient is a PD patient with a homozygous polymorphic genotype having a low catechol O-methyltransferase enzyme activity.
  • wearing off patient refers to a patient experiencing symptoms of end-of-dose wearing off, i.e. shortened duration of the motor response after a PD drug intake and increased severity of e.g. bradykinesia, rigidity, and resting tremor.
  • the term comprises the so-called predictable end-of-dose motor fluctuations characterised by end-of-dose failure of the symptom control.
  • End-of-dose wearing off symptoms may also include fluctuating non motor symptoms, such as anxiety and pain. Motor complications may also include rapid and unpredictable swings from mobility to immobility ("on-off" phenomenon).
  • the terms “repeated dose” and “in a repeated manner” refer to multiple administration of a drug during the day, usually from at least 3 up to 10 times a day, depending on the severity of the disease of a patient with Parkinson's disease and on the subsequent need of levodopa.
  • oral solid dosage form refers to a single unit or multiunit solid oral dosage form.
  • a single unit oral dosage form may be a combination formulation, such as a tablet, which comprises two or more of the drug substances.
  • the single unit oral dosage form is a combination formulation, such as a tablet or a capsule, which comprises all of the drug substances.
  • a multi-unit solid oral dosage form may be a dosage form comprising a plurality of oral solid units in the form of small particles (for instance, a capsule or sachet filled with minitablets, granules or pellets) which, when taken simultaneously or sequentially, provide a unit dose.
  • multiple-unit or multi-particulate oral dosage form may also be used to refer to such a multi-unit solid oral dosage form.
  • the particles may be also be used as such in a so-called sprinkle form that can be sprinkled directly onto food or liquids for easy ingestion.
  • Multiple-unit dosage forms have been accepted to provide advantages over single-unit dosage forms. The pharmacokinetics of the drug release from a multiple-unit dosage form is more uniform than from the single-unit dosage form, because the
  • pharmacokinetics of the drug release from a multiple-unit dosage form is the average value of the kinetics of the drug release from individual subunits.
  • the units of a multiple-unit dosage form may scatter freely in the gastrointestinal tract and act like liquids leaving the stomach within a short period of time, which results in improved biopharmaceutical characteristics, such as improved bioavailability, reduced food effect on plasma profiles and, ultimately, reduced variability of plasma profiles and a lower possibility of local irritation in the gastrointestinal tract.
  • minitablet refers to a compressed pharmaceutical formulation that has dimensions of length and breadth (or, depending on its shape, a diameter) each equal to or less than 5 mm.
  • granule refers to a pharmaceutical formulation in which the ingredients have been mixed together in order to intimately and evenly disperse the drug substance(s) within some or all of the other ingredients and to increase the particle size. Suitable techniques are known in the pharmaceutical industry and can be selected from wet granulation, melt granulation or dry granulation.
  • pellet refers to a substantially spherical solid particle, the diameter of which may range from about 100 microns to about 3 mm, which has been made by layering onto a particle (for instance, on a non-pareil) or by extrusion optionally followed by spheronisation or other similar known techniques. Generally pellets are more spherical in appearance than minitablets.
  • immediate release (IR) dosage form refers to a pharmaceutical dosage form which releases the active ingredient immediately upon administration and will result in 80 - 100 %, preferably 90 - 100 %, dissolution of the dose amount within one hour.
  • the dissolution method is USP apparatus II (paddles): 75 rpm; medium: 0.05 M sodium acetate pH 5.5, 900 ml.
  • the dissolution method is USP apparatus II (paddles): 75 rpm; medium: 0.02 M hydrochloric acid and sodium chloride pH 1.6, 750 ml.
  • immediate release or slightly modified release (IR or slightly MR) dosage form refers to a pharmaceutical dosage form which releases the active ingredient upon
  • dissolution conditions are the same as for carbidopa (see above).
  • solvent refers to solid non-covalent combinations of a solvent and a solute.
  • the solvent can be an organic solvent or water.
  • the solvate can also be referred to as hydrate.
  • hydrate refers to solid non-covalent combinations of water and a solute.
  • the objective of the study was to evaluate the dose effects of 4,5-dihydroxy-2-(4- methylbenzyl)isophthalonitrile and carbidopa on levodopa plasma PK at 3 modified release levodopa strengths (50, 100 and 150 mg).
  • the plasma PK of levodopa after administration of modified release levodopa in combination with carbidopa and 4,5- dihydroxy-2-(4-methylbenzyl)isophthalonitrile was compared to the standard
  • levodopa/carbidopa Sinemet®
  • Carbidopa and 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile were administered q.i.d for 7 days and on the 7 th day levodopa was added into the treatment. There was a wash-out for at least 4 days between the treatment periods.
  • peripheral venous blood samples were drawn frequently for determination of levodopa, carbidopa, the levodopa metabolite 3- O-methyldopa and 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile concentration in plasma.
  • the concentrations were determined with validated LC-MS/MS method.
  • the primary PK variable for the evaluation of levodopa PK was AUCo-24 h to describe the total levodopa plasma exposure.
  • the secondary PK variable was C min,taU to describe minimum plasma concentrations of levodopa during the dosing intervals.
  • the PK variables were analysed using a mixed linear model with a 90 % confidence interval (Cl) applicable for the crossover design.
  • the statistical model included treatment and period as fixed effects and subject as a random effect.
  • the objective of the study was to evaluate the plasma pharmacokinetics (PK) of orally administered modified release levodopa in combination with carbidopa and 4,5-dihydroxy-2- (4-methylbenzyl)isophthalonitrile compared to the standard levodopa/carbidopa/entacapone (Stalevo®) containing 100 mg of levodopa.
  • PK plasma pharmacokinetics
  • the primary PK variable for the evaluation of levodopa PK was peak-through fluctuation for each dosing interval (PTF tau ).
  • the secondary PK variables were and
  • Example 4 The levodopa pellets according to the invention are described in table 4 and the granules made of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile and carbidopa in table 5.
  • Table 4 Levodopa pellets Pellet ingredients are mixed in a high shear mixer. Purified water is added after which the formed wet mass is extruded in twin-screw or basket type extruder. The extrudate is charged and spheronised in a spheronizer. The spheres obtained from the spheronizer are dried in fluid bed dryer or on trays. Finally, the pellets are screened. The screened pellets may be lubricated with talc. Table 5. Granules made of 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile and carbidopa
  • Granule components are mixed in a high shear mixer. Granulation liquid is sprayed in the powder blend.
  • the binder polyvinylpyrrolidone
  • the binder may be dissolved in purified water, added as a powder or a combination thereof.
  • the granules are dried in a fluid bed dryer and screened with a conical mill.
  • the granules may be lubricated by adding extragranular magnesium stearate.
  • Granules and pellets are encapsulated, compressed into tablets or filled into sachets.
  • Granule components are mixed in a fluid bed granulator.
  • Granulation liquid is sprayed in the powder blend.
  • the granules are dried in a fluid bed granulator.
  • the granules are lubricated. Fast dissolution rate is achieved with compositions 1 and 2.
  • Porous granules are achieved with compositions 3 and 4.
  • Granule components are mixed in a high shear mixer. Granulation liquid is sprayed in the powder blend. After liquid addition, the granules are dried in a fluid bed granulator. After sieving, the granules are lubricated. Larger granules are achieved with composition 5. Granules with good flowability are achieved with composition 6. Granules with superior compactibility are achieved with composition 7.
  • Granule components are fed into a continuous mixer. Powder blend is granulated with granulation liquid in a twin-screw granulator. The granules are dried in a fluid bed. After sieving, the granules are lubricated. Granules with bimodal particle size distribution are achieved. Granules with good compactibility are achieved with composition 10. Porous granules are achieved with compositions 11 and 12.
  • Pellet components are mixed in a high shear mixer.
  • Optional binder or release modifying agent is added dissolved in purified water, as a powder or a combination thereof
  • compositions 19 and 20 compositions 19 and 20.
  • the formed wet mass is extruded in twin- screw or basket type extruder.
  • the extrudate is charged and spheronised in a spheronizer.
  • the spheres obtained from the spheronizer are dried in fluid bed dryer or on trays.
  • blend is screened and the pellets retained on 0.5-mm screen are collected.
  • the final blend is prepared by blending the screened pellets with talc or colloidal silica. Pellets are hard and round with slightly modified or immediate release.
  • Micronised levodopa is dispersed in a water solution of polyvinylpyrrolidone or other binder and then colloidal silica is added. Levodopa suspension is layered on top of sugar
  • composition 22 or microcrystalline cellulose (composition 23) beads of size 100-1,500 pm. Layering is performed in fluid bed coater. Pellets are hard and round with immediate release.
  • Pellets are manufactured with extrusion spheronisation or fluid bed layering and coated in fluid bed coater (Wurster or FlexStream) for modifying the release. Coating thickness is 4-15 % (weight gain). Coating liquid is aqueous or organic. Pellets are hard and round with slightly modified or modified release.
  • Granule components are mixed in a high shear mixer. Granulation liquid is sprayed in the powder blend. Binder is added dissolved in purified water, as a powder or a combination thereof. After liquid addition, the granules are dried in a fluid bed dryer or on trays. After sieving, the granules are lubricated. With compositions 31, 32 and 33, release is modified, slightly modified and immediate, respectively.
  • Levodopa, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, crospovidone and optionally hypromellose or hydroxyethylcellulose and optionally sodium lauryl sulphate are mixed in a suitable blender or the ingredients are fed to a ring layer granulator with multiple gravimetric feeders. Then granulation liquid (purified water or purified water with crospovidone and optionally sodium lauryl sulphate) is added to the ring layer granulator. The wet mass is fed to a radial extruder for extrusion. The extrudates are conveyed to a spheronizer. The spheronized pellets are dried in a fluid bed dryer. After drying, optionally talc is added onto the dry pellets with subsequent mixing in the fluid bed.
  • granulation liquid purified water or purified water with crospovidone and optionally sodium lauryl sulphate
  • Levodopa, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose and crospovidone or gelatin and optionally sodium lauryl sulphate are mixed in a high shear mixer. Then granulation liquid (purified water or purified water with sodium lauryl sulphate and crospovidone or gelatin) is sprayed in the mixed powder blend. A predetermined amount of granulation liquid is used, after which a wet massing phase is possibly needed. The wet granules are dried and optionally sieved. Sodium stearyl fumarate or magnesium stearate is added and mixed with the granules. The dried granules are compressed into minitablets. Optionally talc is added. Minitablets are up to 4 mm in diameter and can be encapsulated in hard gelatin or hypromellose capsule shells.
  • the aforementioned granules, pellets and optionally talc are encapsulated in hard gelatin or hypromellose capsule shells.
  • Example 16 The aforementioned granules, pellets and optionally filler, disintegrant and/or lubricant are blended and then compressed into tablets. The tablets might be coated.
  • the aforementioned granules, pellets and optionally lubricant are blended and then filled into sachets.

Abstract

La présente invention concerne le 4,5-dihydroxy-2-(4-méthylbenzyl)isophtalonitrile, la carbidopa et la lévodopa destinés à être utilisés dans une méthode de traitement de la maladie de Parkinson ainsi que des formes posologiques pharmaceutiques utilisées dans ladite méthode.
PCT/FI2018/050834 2017-11-16 2018-11-15 Nouvelle utilisation et nouvelles formes posologiques pharmaceutiques WO2019097120A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2020020969A1 (fr) * 2018-07-25 2020-01-30 Orion Corporation Solvates de 4,5-dihydroxy-2-(4-méthylbenzyl) isophthalonitrile et leurs formes cristallines

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