WO2018007556A1 - Dispersion solide pharmaceutique d'un inhibiteur de bcl-2, compositions pharmaceutiques associées et utilisations dans le traitement du cancer - Google Patents

Dispersion solide pharmaceutique d'un inhibiteur de bcl-2, compositions pharmaceutiques associées et utilisations dans le traitement du cancer Download PDF

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WO2018007556A1
WO2018007556A1 PCT/EP2017/067015 EP2017067015W WO2018007556A1 WO 2018007556 A1 WO2018007556 A1 WO 2018007556A1 EP 2017067015 W EP2017067015 W EP 2017067015W WO 2018007556 A1 WO2018007556 A1 WO 2018007556A1
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solid dispersion
pharmaceutical composition
oral administration
cancer
pharmaceutical
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PCT/EP2017/067015
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English (en)
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Caroline CHEMIN
Jean-Manuel Pean
Daya Verma
Ulrich Meier
Emeric Reynaud
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Les Laboratoires Servier
Novartis Ag
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Publication of WO2018007556A1 publication Critical patent/WO2018007556A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the invention relates to a solid dispersion pharmaceutical intermediate comprising N-(4- hydroxyphenyl)-3 - ⁇ 6 -[(( ⁇ - ⁇ -(4-morpholinylmethyl)-3 ,4-dihydro -2( 1 H)- isoquinolinyl)carbonyl]-l ,3-benzodioxol-5-yl ⁇ -N-phenyl-5,6,7,8-tetrahydro-l-indolizine carboxamide, referred to herein as 'Compound A', or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions for oral administration comprising said solid dispersion pharmaceutical intermediate.
  • the invention also relates to the use of such compositions for the treatment of cancer, diseases of the immune system and auto-immune diseases.
  • Compound A in the form of a hydrochloride salt ('Compound A.HC1') is specifically disclosed in this document.
  • Compound A as a free base or hydrochloride salt thereof, is a poorly water-soluble drug, i.e. its solubility is lower than 0.1 mg/mL at acidic and neutral pH, which poses a challenge for oral bioavailability and therapeutic effect. It is classified as a BCS II (low soluble and highly permeable) drug substance, thus its absorption is only limited by its solubility.
  • the present invention relates to solid dispersion pharmaceutical intermediates of Compound A and pharmaceutical compositions comprising such solid dispersion pharmaceutical intermediates, which enable increased drug exposure. They have the benefit of being obtained starting from Compound A prepared by any suitable process, wherein Compound A can be present as the free molecule or addition salts with a pharmaceutically acceptable acid or base.
  • Compound A is solubilized with the selected polymer in one or a mixture of solvents, allowing complete dissolution of the constituents to be obtained, and then the resulting solution is spray-dried and the solvent(s) is (are) evaporated off.
  • Alternative suitable manufacturing techniques include solvent evaporation, kneading, melt congealing and co- precipitation.
  • Figure 1 Compound A concentrations and PK parameters in plasma after a single oral dose of 100 mg Compound A in the formulation of Examples 2 and 3.
  • Figure 2 Compound A plasma concentration-time courses in dogs after a single oral dose of 100 mg Compound A in the formulation of Examples 2 and 3.
  • solid dispersion pharmaceutical intermediate means an amorphous drug substance dispersed in a polymeric solid matrix carrier.
  • This form of intermediate is intended to be formulated into a pharmaceutical composition in the form of a pharmaceutical dosage form, to promote dissolution of the drug substance in the gastrointestinal tract and maintain the drug in a super-saturated state in order to be absorbed.
  • Solid dispersion pharmaceutical intermediates are produced by techniques known in the art, for example, spray drying, solvent evaporation, kneading, co-precipitation, hot melt extrusion, and melt congealing.
  • solid dispersion polymers means a polymer suitable for obtaining a stable solid dispersion of the drug substance in amorphous form in reproducible and industrially feasible manner, or a mixture of polymers thereof.
  • the drug substance molecules are distributed in a solid matrix which prevents them from forming a crystal lattice.
  • the following solid dispersion polymers may be used according to the invention: (i) vinyl polymers including polyvinyl esters (such as polyvinyl acetate phthalate) as well as polyvinylpyrrolidone based homo- and co-polymers (e.g. polyvinylpyrrolidone (PVP), e.g.
  • PVP K30 which may be obtained from BASF
  • copovidone i.e. vinylpyrro lido ne -vinyl acetate copolymer, e.g. Kollidon® VA64 which may be obtained by BASF
  • polyvinyl capro lactam-polyvinyl acetate- polyethylene glycol graft co-polymer e.g. Soluplus® which may be obtained from BASF
  • cellulosic compounds including cellulosic ethers or esters such as methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), and hydroxypropylcellulose (HPC) compounds, and more especially HPMC E5 (e.g.
  • Methocel® E5 which may be obtained from Dow
  • HPMC E15 which may be obtained from Ashland
  • HPMC-3CPS which may be obtained from Dow
  • Klucel® EF which is an HPC and may be obtained from Ashland
  • HPMC acetate succinate HPMC-AS
  • HPMC- P HPMC phthalate
  • polymethacrylates or copolymers of methacrylic acid which correspond to a completely polymerised copolymer of methacrylic acid and acrylic or methacrylic ester (e.g. Eudragit® which may be obtained from Evonik).
  • the solid dispersion pharmaceutical intermediate of the invention may be formulated together with one or more further pharmaceutically acceptable inactive ingredients, commonly also referred to as pharmaceutical excipients, e.g. fillers, disintegrants, lubricants, glidants, to form the pharmaceutical composition for oral administration.
  • pharmaceutical excipients e.g. fillers, disintegrants, lubricants, glidants
  • 'x90 particle size' means the particle dimension corresponding to 90% of the cumulative undersize distribution. Tests may be carried out, for example, using laser light diffraction.
  • Optional fillers are well known to the skilled formulator.
  • Optional fillers include lactose, mannitol (e.g. Mannitol DC, being suitable for direct compression tableting), sorbitol, glucose, dextrose, calcium carbonate, calcium phosphate, hydroxypropylmethyl cellulose (HPMC) and micro crystalline cellulose (Cellulose MK GR).
  • Disintegrants are well known to the skilled formulator.
  • optional disintegrants include cross-linked sodium carboxymethylcellulose (Na-CMC XL also known as 'natrium-CMC XL' or 'sodium-CMC-XL', or 'croscarmellose sodium'), starch or modified starches, such as sodium starch glycolate, maize starch and crospovidone (i.e. cross-linked polyvinyl pyrrolidone, e.g. Plasdone XL 10 which may be obtained from Ashland).
  • Lubricants are well known to the skilled formulator.
  • optional lubricants include stearic acid, magnesium stearate, stearyl fumarate, talc, glyceryl behenate and ricinus oil.
  • Glidants are well-known to the skilled formulator.
  • optional glidants include silica (e.g. Aerosil® 200 which may be obtained from Evonik), magnesium stearate, talc.
  • composition for oral administration means for example a tablet or capsule, in particular a tablet. Such tablet may optionally be film-coated.
  • 'Compound A.HC1' or 'Compound A.HC1 salt' means the hydrochloride salt of N-(4- hydroxyphenyl)-3- ⁇ 6-[((35')-3-(4-morpholinylmethyl)-3,4-dihydro-2(lH)- isoquinolinyl)carbonyl]-l ,3-benzodioxol-5-yl ⁇ -N-phenyl-5,6,7,8-tetrahydro-l -indolizine carboxamide.
  • the term 'comprising' means 'including', and is not intended to exclude the presence of any additional component, unless the context suggests otherwise, for example when the components together sum to 100%.
  • 'solvent' means a solvent capable of dissolving Compound A and the selected polymer(s). Preference will be given to: (i) polar protic solvents such as alcohols and more especially methanol and ethanol; (ii) apolar protic solvents such as acetone and dichloromethane; (iii) mixtures of those solvents; or (iv) mixtures of those solvents with water.
  • polar protic solvents such as alcohols and more especially methanol and ethanol
  • apolar protic solvents such as acetone and dichloromethane
  • mixtures of those solvents or (iv) mixtures of those solvents with water.
  • 'Cancer' means a class of disease in which a group of cells display uncontrolled growth. Cancer types include haematological cancer (lymphoma and leukemia) and solid tumors including carcinoma, sarcoma, or blastoma.
  • 'Cancer' includes cancer of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the ossophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.
  • 'free molecule' and 'free base' are used interchangeably herein and refer to Compound A when not in salt form.
  • a solid dispersion pharmaceutical intermediate comprising N-(4-hydroxyphenyl)-3- ⁇ 6- [((35 -3 -(4-morpholinylmethyl)-3 ,4-dihydro-2( 1 H)-isoquinolinyl)carbonyl] - 1 ,3 - benzodioxol-5 -yl ⁇ -N-phenyl-5 ,6 ,7 ,8 -tetrahydro - 1 -indolizine carboxamide (Compound A), as the free molecule or pharmaceutically acceptable salt, and one or more solid dispersion polymers.
  • E3.A solid dispersion pharmaceutical intermediate according to embodiment 2 comprising from 20% to 50% by weight of Compound A free molecule or pharmaceutically acceptable salt.
  • a solid dispersion pharmaceutical intermediate according to embodiment 3 comprising from 35% to 45%, preferably 40%, by weight of Compound A free molecule or pharmaceutically acceptable salt.
  • E6. A solid dispersion pharmaceutical intermediate according to any one of embodiments 1 to 5, comprising a solid dispersion polymer selected from polyvinyl capro lactam-polyvinyl acetate-polyethylene glycol graft co-polymer (for example Soluplus®), polyvinylpyrrolidone K30 (PVP K30), hydroxypropylmethylcellulose E5 (HPMC E5), hydroxypropylcellulose (for example Klucel® EF), hydroxypropylmethylcellulose acetate succinate (for example Aqoat®) and copovidone (for example Kollidon® VA64), preferably the solid dispersion polymer is selected from polyvinylpyrrolidone K30 (PVP K30), hydroxypropylmethylcellulose E5 (HPMC E5), hydroxypropylmethylcellulose acetate succinate (Aqoat®) and copovidone
  • one solid dispersion polymer which is copovidone (Kollidon® VA64) or hydroxypropylmethylcellulose acetate succinate (Aqoat®).
  • a pharmaceutical composition for oral administration comprising the solid dispersion pharmaceutical intermediate of any of embodiments 1 to 10, in an amount by weight of total composition of from 10% to 80%, in particular from 10% to 50%.
  • a pharmaceutical composition for oral administration according to embodiment 11 comprising the solid dispersion pharmaceutical intermediate in an amount by weight of total composition of from 20% to 30%, in particular from 22 to 26%.
  • at least one filler selected from lactose, mannitol, calcium carbonate, calcium phosphate, hydroxypropylmethyl cellulose (HPMC) and microcrystalline cellulose (Cellulose MK GR).
  • a pharmaceutical composition for oral administration according to embodiments 11 , 12 or 13 comprising one or more fillers, the total amount of fillers being from 10 to 90%, in particular from 30% to 90% by weight of total composition, more particularly from 55% to 67%.
  • a. mannitol in an amount of from 30% to 35% by weight
  • cellulose MK GR in an amount of from 30% to 35% by weight.
  • disintegrant selected from cross-linked sodium carboxymethylcellulose (Na-CMC XL), sodium starch glycolate, maize starch and crospovidone (Plasdone XL10).
  • a pharmaceutical composition for oral administration according to embodiment 21 comprising a disintegrant in an amount by weight of from 7 to 13%, in particular 10%.
  • the total amount of glidant is present in an amount by weight of from 0.1% to 5%.
  • E28 A pharmaceutical composition for oral administration according to any of embodiments 11 to 27, wherein said composition comprises a lubricant.
  • composition comprises a lubricant selected from stearic acid, magnesium stearate, stearyl fumarate, talc, glyceryl behenate and ricinus oil.
  • a lubricant selected from stearic acid, magnesium stearate, stearyl fumarate, talc, glyceryl behenate and ricinus oil.
  • a pharmaceutical composition for oral administration according to any of embodiments 1 1 to 32 comprising from 5 mg to 150 mg of Compound A free molecule, in particular 25 mg, 50 mg, 75 mg and 100 mg.
  • a pharmaceutical composition for oral administration comprising:
  • a pharmaceutical composition according to embodiment 34 which is a tablet, comprising:
  • ⁇ a filler selected from mannitol DC and lactose.
  • a tablet for oral administration according to any of embodiments 35 to 37 comprising from 5 mg to 150 mg of Compound A free molecule, in particular 25 mg, 50 mg, 75 mg and 100 mg.
  • E39. A method of modulating Bcl-2 receptor activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the composition according to any of embodiments 11 to 38.
  • E40 A method of treating a disorder or disease selected from cancers, diseases of the immune system and auto-immune diseases, comprising administering to the subject a therapeutically effective amount of the composition according to any of embodiments 1 1 to 38.
  • E41 A method according to embodiment 40 wherein the cancer is selected from cancer of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the ossophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small- cell lung cancer, prostate cancer and small-cell lung cancer.
  • E42 A pharmaceutical composition according to any one of embodiments 1 1 to 38, for use as a medicament.
  • cancer is selected from cancer of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the ossophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.
  • a combination comprising:
  • compositions according to any one of embodiments 11 to 38, and one or more therapeutically active agents, for simultaneous, sequential or separate use.
  • a process for the preparation of a solid dispersion pharmaceutical intermediate according to any of embodiments 1 to 10 consisting of (i) mixing Compound A, or a pharmaceutically acceptable salt thereof, with a solid dispersion polymer in one or more solvents, (ii) spray-drying the resulting solution, and (iii) evaporating off the solvent(s).
  • a further embodiment provides a pharmaceutical composition for oral administration according to any one of the embodiments herein, wherein said composition optionally comprises a surfactant selected from poloxamer, e.g. Kolliphor PI 88 (which may be obtained from BASF), sodium lauryl sulfate, polysorbate 80 (Tween 80), Tween 20, Polyoxyl 35 Hydrogenated Castor oil, e.g. Kolliphor® ELP and (which may be obtained from BASF).
  • a further embodiment provides a pharmaceutical composition for oral administration according to any one of the embodiments herein, wherein said composition optionally comprises a binder selected from Povidone (e.g. PVP K30), Malto dextrine (e.g. Lycatab® DSH, e.g. by Roquette), HPMC (e.g. Pharmacoat® 606 e.g. by Shin-Etsu) and HPC (e.g. HPC-L).
  • a binder selected from Povidone (e.g. PVP K30), Malto dextrine (e.g. Lycatab® DSH, e.g. by Roquette), HPMC (e.g. Pharmacoat® 606 e.g. by Shin-Etsu) and HPC (e.g. HPC-L).
  • Povidone e.g. PVP K30
  • Malto dextrine e.g. Lycatab® DSH, e.g. by Roquette
  • HPMC e.g. Pharmacoat® 60
  • a further embodiment provides a pharmaceutical composition for oral administration according to any one of the embodiments herein, wherein said composition optionally comprises a film coating.
  • Tablet film coatings are an optional embodiment of the present invention. They can be selected to prevent moisture uptake and/or abrasion, and provide a physical barrier between the active drug substance and the external environment.
  • the skilled formulator can select appropriate film coatings according to those well-known in the art.
  • HPMC or PVA based coatings can be used, such as Opadry ⁇ (HPMC based), Opadry II ® (PVA based) and OpadryAMB II ⁇ (PVA based).
  • the solid dispersion pharmaceutical intermediates described herein may be used to provide compositions which enable an increased bioavailability of Compound A.
  • certain embodiments of the present invention have surprisingly been found to provide additional advantages.
  • polymers polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft co-polymer (Soluplus®), polyvinylpyrrolidone ( PVP K30), hydroxypropylmethylcellulose (HPMC E5), HPC (Klucel® EF), HPMC acetate succinate (Aqoat®) or vinylpyrrolidone -vinyl acetate copolymer (Kollidon® VA64) in the solid dispersion pharmaceutical intermediate, a low rate of degradation and no crystallisation of Compound A is observed, and particularly for polyvinylpyrrolidone ( PVP K30), hydroxypropylmethylcellulose (HPMC E5), HPC (Klucel® EF), HPMC acetate succinate (Aq
  • polymers polyvinyl caprolactam- polyvinyl acetate -polyethylene glycol graft co-polymer (Soluplus®), polyvinylpyrrolidone (PVP K30), hydroxypropylmethylcellulose (HPMC E5), HPMC acetate succinate (Aqoat®) and vinylpyrrolidone -vinyl acetate copolymer (Kollidon® VA64) enable high exposures in rats, particularly polyvinylpyrrolidone (PVP K30), hydroxypropylmethylcellulose (HPMC E5), HPMC acetate succinate (Aqoat®) and vinylpyrrolidone -vinyl acetate copolymer ( Kollidon® VA64).
  • certain components or quantities of components have been found to provide unexpected benefits.
  • a further unexpected advantage has been identified when using mannitol and cellulose fillers in a ratio of around 1 : 1 , as described in the embodiments herein. Such ratios improve the flowability of the composition, reducing or avoiding gelling. Gelling can complicate manufacturing and could also retard the release of Compound A. Examples
  • Example 1 Solid dispersion pharmaceutical intermediate comprising Compound A.HC1
  • Composition (% weight): Compound A.HC1 salt 40% Kollidon® VA64 60%
  • Methanol (19.584kg) and acetone (19.584kg) are charged into a vessel and agitated at room temperature.
  • Compound A.HC1 (1kg) is added and the mixture agitated until the solution becomes clear.
  • Kollidon ® VA64 (1.5kg) is then added and the mixture agitated until the solution becomes almost clear.
  • Spray drying Depending on the batch size the feed solution can be spray dried using different equipment with varying spray drying parameters. Typical process parameters are described below:
  • Spray drying inlet temperature 90-180°C, outlet temperature 60-70°C (target 65°C), feed rate 10-30 (kg/h), process gas flow 360Kg/hr.
  • the device and spray drying parameters may be modified as necessary.
  • Typical parameters for secondary vacuum drying temperature 60-70°C, drying pressure ⁇ 10 [mbar abs], nitrogen gas sweep optional. Drying conditions can be varied with batch size. For example, solid dispersion particles may be dried from 45 to 70°C under vacuum using partially a nitrogen gas flow for the larger batches, until the specifications with respect to residual solvent and water content are met.
  • the x90 particle size of the solid dispersion intermediate obtained from the process described hereinabove is typically from 20 to 35 microns.
  • Example 2 Clinical Service Formulation 2 QCSF2A') Tablet comprising mannitol
  • Example 3 Tablet comprising lactose
  • Example 4 PK in pentagastrin-pre-treated dogs after oral administration of Compound A.HC1 salt
  • the objective of this study was to determine a concentration-time course and evaluate the pharmacokinetic parameters of Compound A.HC1 salt in pentagastrine-pretreated male Beagle dogs after lOOmg Compound A oral dosing of the formulations of Example 2 and Example 3 herein.
  • the tablets of both Example 2 and 3 were coated with Opadry (HPMC) for use in this study. Animals
  • pentagastrin (6 g/kg) was administered via intramuscular route.
  • pentagastrin was freshly dissolved in PEG400, then water added under constant stirring to achieve 10% (v/v) PEG400 solution (PEG400:water, 1 :9, v:v) with the final pentagastrin concentration of 80 ⁇ g/mL.
  • the dosing volume was 0.075 mL/kg intramuscular using a 23 G needle.
  • the wash-out period between each dosing session was at least 3 days.
  • Formulations were administered by deep throat application of 4 tablets of total 100 mg Compound A per dog followed by a 20 mL rinse with drinking water.
  • Blood ( ⁇ 1 mL/time point) was collected from the vena cephalica in EDTA-coated Eppendorf tubes at time points presented in the following table. After collection, the blood samples were immediately put on ice. The blood was centrifuged within 15 min after collection (3000 g, 10 min, 4°C). Plasma was prepared and stored at -80°C until sample analysis determination.
  • EDTA ethylenediaminetetraacetic acid
  • Compound A plasma concentrations were measured.
  • the LLOQ (lower limit of quantification) of Compound A was 0.200ng/mL using 20 ⁇ L of plasma.
  • Example 2 Following administration of 100 mg/dog Compound A in the composition of Example 2 (CSF2A), plasma exposure amounted to mean Cmax/Dose of 40.7 ⁇ 24.3 ng/mL/(mg/kg) and to mean AUClast/Dose of 134 ⁇ 55.3 h-ng/mL/(mg/kg).
  • Example 5 Alternative solid dispersion pharmaceutical intermediates comprising Compound A.HC1
  • composition (% weight):
  • Example 5 Solid dispersion pharmaceutical intermediates obtained in Example 5 allows to stabilize Compound A.HC1 in amorphous form in denaturing storage conditions, i.e. 40°C / 75% RH and 50°C, for 1 month.
  • Example 7 PK in rats after oral administration of suspensions of Compound A.HC1 prepared from solid dispersion pharmaceutical intermediates obtained in Example 6
  • the objective of this study is to determine the pharmacokinetic parameters measured in rats after 100 mg/kg Compound A oral dosing.
  • Suspensions are prepared by dissolving the solid dispersion pharmaceutical intermediates of Example 5 in 1% HEC (Hydroxyethyl Cellulose) in purified water. Animals and Compound A.HC1 dose levels
  • the rats were dosed by gavage with a volume of 10 mL/kg.
  • Blood samples (approximately 0.1 mL) were collected at room temperature from the caudal vein into sodium heparinate tubes at 30 min, 1 h, 2 h, 4 h, 8 h and 24 h post-administration. Just after each drawing, blood was centrifuged to obtain plasma and stored frozen at a temperature of - 70°C or below, in hermetically sealed plastic tubes. Assay
  • composition per tablet without film coating ( % weight per weight of tablet):
  • Aerosil 200 (glidant) 0.5000%
  • composition per tablet with film coating (% weight per weight of tablet):
  • Example 9 Clinical Service Formulation 1 'CSFl') Tablet comprising Compound A.HC1 (standard formulation)
  • the micronised product is mixed with sodium laurilsulfate. Then, the premix is added to micro crystalline cellulose, lactose monohydrate, croscarmellose sodium and hydroxypopylcellulose. The mixing is granulated using wet granulation (conventional manufacturing process) in a planetary granulator. After being dried in the planetary granulator or in an oven system, the granulate is sifted. Magnesium stearate (lubricant) and silica (glidant) are then added for the external phase: the lubricated granulate is sifted and compressed to obtain the tablets. Finally, tablets are film-coated with a white premix (Sepifilm No. 37781 RBC).
  • composition per tablet with film coating (% weight per weight of tablet):

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Abstract

L'invention concerne des préparations de dispersion solide pharmaceutique de composé A : (I), ainsi que l'utilisation de ces préparations dans le traitement du cancer.
PCT/EP2017/067015 2016-07-07 2017-07-06 Dispersion solide pharmaceutique d'un inhibiteur de bcl-2, compositions pharmaceutiques associées et utilisations dans le traitement du cancer WO2018007556A1 (fr)

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EP2829545A1 (fr) * 2013-07-23 2015-01-28 Les Laboratoires Servier Nouveaux derives phosphates, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

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