WO2021239893A1 - Dispersion solide amorphe d'acalabrutinib - Google Patents

Dispersion solide amorphe d'acalabrutinib Download PDF

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WO2021239893A1
WO2021239893A1 PCT/EP2021/064235 EP2021064235W WO2021239893A1 WO 2021239893 A1 WO2021239893 A1 WO 2021239893A1 EP 2021064235 W EP2021064235 W EP 2021064235W WO 2021239893 A1 WO2021239893 A1 WO 2021239893A1
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asd
acalabrutinib
pdf
disppol
hpmcas
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PCT/EP2021/064235
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English (en)
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Aaron Stewart
Deanna MUDIE
Nishant BISWAS
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Bend Research, Inc.
Lonza Ltd
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Publication of WO2021239893A1 publication Critical patent/WO2021239893A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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

Definitions

  • This invention discloses amorphous solid dispersions ASDs comprising acalabrutinib and a dispersion polymer, pharmaceutical dosage forms PDFs comprising said ASD, such as capsules, tablets or caplets, and a method for preparing said ASDs.
  • Acalabrutinib with CAS 1420477-60-6 is a tyrosine kinase inhibitor TKI and is used to treat a type of non-Hodgkin lymphoma known as mantle cell lymphoma.
  • CALQUENCE® is the reference listed drug product for acalabrutinib in its crystalline Form I as active pharmaceutical ingredient. The Area Under the Curve AUC of CALQUENCE is reduced when taken concomitantly with a CYP3 A inducer, proton pump inhibitor PPI, antacid or H2- receptor antagonist.
  • the CALQUENCE FDA label states to avoid co-administration with a PPI.
  • a gastric acid reducing agent cannot be avoided, it suggests separating dosing by at least 2 h when taking an antacid or taking CALQUENCE 2 h before taking an H2 -receptor antagonist. Since gastric reducing agents are extensively used during TKI therapy this drug interaction can negatively impact treatment and quality of life.
  • Said form of acalabrutinib should be suitable for preparing pharmaceutical dosage forms PDFs, such as solid dosage forms SDFs, the PDFs comprising said form of acalabrutinib.
  • acalabrutinib in form of an amorphous solid dispersion (ASD) significantly increases solubility compared to Form I of acalabrutinib such that solubility and dissolution rate are high enough to achieve a higher extent of dissolution and therefore AUC at both low and elevated pH.
  • Pharmaceutical dosage forms PDFs comprising an ASD according to the invention provide a solubility boost at elevated gastric pH and prevent precipitation, such as in vitro or in vivo precipitation, which helps to reduce variability. Gastric pH dependency is thereby reduced and dissolution rates are improved.
  • the Calquence capsule is a wholly or partially filled with a ten mm and ten mm.
  • the Calquence capsule is a wholly open length of 19.4 mm and an average external diameter of 6.96 mm (capsule cap) and 6.63 mm (capsule body).
  • tablet PDFs may have a diameter of 11 mm and a thickness of 4.8 mm (standard round concave shape).
  • the use of the ASD according to the invention may therefore lead to a reduction in some of the warnings in the prescribing information, thereby providing more flexibility for the patient and may provide opportunities to treat patients that would otherwise disqualify due to concomitant treatments.
  • ASDs according to the invention may also yield once daily regimen, e.g. using a controlled release formulations.
  • amorphous an amorphous solid is any noncrystalline solid in which the atoms and molecules are not organized in a definite lattice pattern API active pharmaceutical ingredient
  • ASD amorphous solid dispersion a solid dispersion including an active pharmaceutical ingredient molecularly dispersed in a polymer, in instant invention in DISPPOL, wherein the active pharmaceutical ingredient is amorphous or substantially (at least 80 %, preferably at least 90 %, more preferably at least 95 %, the % being weight percent and being based on the total weight of the active pharmaceutical ingredient) amorphous.
  • DC IV dichloromethane A system in which molecules, e.g., molecules of an active pharmaceutical ingredient, are distributed within a continuous phase of a different composition.
  • a solid dispersion is a system in which at least one solid component is distributed throughout another solid component dispersion polymer
  • an excipient may be incorporated in a pharmaceutical composition.
  • An excipient can be used, for example, to dilute an active pharmaceutical ingredient and/or to modify properties of a pharmaceutical composition.
  • Excipients may be such that are conventionally used in the preparation of pharmaceutical compositions, they are known to the skilled person
  • PMMAMAA or PMMAMA an example is Eudragit L100® (Evonik Industries
  • Subject of the invention is an amorphous solid dispersion ASD comprising acalabrutinib in amorphous form and a dispersion polymer DISPPOL.
  • Figure 1 PXRD diffractogram showing the amorphous nature of ASD-50-H.
  • Figure 2 pH 5.0 to 6.5, i.e. gastric medium GASTMED-5 to intestinal medium (2-1) 25/75 Acalabrutinib/HPMCAS-H as ASD-25-H
  • Figure 3 pH 5.0 to 6.5, i.e. gastric medium GASTMED-5 to intestinal medium (3-1) 50/50 Acalabrutinb/HPMCAS-H as ASD-50-H
  • Figure 4 pH 6.0 to 6.5, i.e. gastric medium GASTMED-6 to intestinal medium (4-1) 25/75 Acalabrutinib/HPMCAS-H as ASD-25-H
  • Figure 5 pH 6.0 to 6.5, i.e. gastric medium GASTMED-6 to intestinal medium (5-1) 50/50 Acalabrutinb/HPMCAS-H as ASD-50-H
  • Figure 8 test results for the transition from pH 6.0 to pH 6.5 (8-1) ASD tablet (8-2) Calquence capsule
  • Dashed lines are non-reversing signals.
  • ASD-25-M (9-2) ASD-25-H (9-3) ASD-50-H (9-4) ASD-50-M Solid lines are reversing signals.
  • Figure 10 test results for the transition from pH 6.0 to pH 6.5 (10-1) Acalabrutinib Form I (10-2) ASD-50-K30
  • Figure 11 DSC thermogram of ASD-50-K30 before and after aging for 28 days at 40 °C/75% RH.
  • Figure 12 Dissolved acalabrutinib as a function of time in the presence of different polymers, concentration versus time (12-1) No polymer (12-2) PVP-K30 (12-3) PVP-VA64 (12-4) HPMCAS-L (12-5) HPMC E3 (12-6) Eudragit L100 (12-7) HPMCAS-H (12-8) HPMCAS-M
  • Figure 13 Scattering as a function of time showing the onset of precipitation in the presence of different polymers, scattering versus time.
  • Figure 14 test results for the transition from pH 6.0 to pH 6.5 (14-1) Acalabrutinib Form I (14-2) ASD-50-VA64
  • Figure 15 test results for the transition from pH 6.0 to pH 6.5 (15-1) Acalabrutinib Form I (15-2) ASD-50-VA64
  • Fig 15 shows part of the test results of Fig 14 during the time in intestinal buffer with enlarged Y-scaling
  • Figure 16 Schematic of the artificial stomach-duodenum -jejunum dissolution apparatus
  • Figure 17 Dissolved acalabrutinib in stomach compartment containing GASTMEDEX-2 medium.
  • Figure 18 Dissolved acalabrutinib in duodenum compartment after transfer from GASTMEDEX-2 medium.
  • Figure 19 Dissolved acalabrutinib in stomach compartment containing GASTMEDEX-6 medium.
  • Figure 20 Dissolved acalabrutinib in duodenum compartment after transfer from GASTMEDEX-6 medium.
  • Figure 21 Acalabrutinib plasmas concentration versus time.
  • Acalabrutinib comprises its free base and any pharmaceutically relevant salt.
  • the ASD comprises less than 10 wt%, preferably less than 5 wt%, more preferably less than 1 wt%, of crystalline acalabrutinib; the wt% being based on the weight of the ASD.
  • the ASD comprises less than 10 wt%, preferably less than 5 wt%, more preferably less than 1 wt%, of crystalline acalabrutinib; the wt% being based on the weight of the acalabrutinib.
  • the acalabrutinib is dispersed in the ASD.
  • the acalabrutinib is dissolved in the ASD.
  • the acalabrutinib is homogeneously or substantially homogeneously dispersed throughout the dispersion polymer.
  • the ASD is a molecular dispersion of acalabrutinib and DISPPOL.
  • Acalabrutinib may be amorphous or substantially amorphous in ASD; substantially means that at least 90 wt%, preferably at least 95 wt%, more preferably at least 99 wt%, of acalabrutinib is amorphous; the wt% being based on the total weight of acalabrutinib in ASD.
  • ASD therefore may be an amorphous ASD.
  • the amorphous nature of acalabrutinib may be evidenced by a lack of sharp Bragg diffraction peaks in the x-ray pattern when ASD is analyzed by a powder X-Ray Diffraction (PXRD).
  • Possible parameters and settings for a x-ray diffractometer are equipment with a Cu-Kalpha source, setting in modified parallel beam geometry between 3 and 40° 2Theta and a scan rate of 2°/min with a 0.0° step size.
  • Another evidence for the amorphous nature of acalabrutinib in the ASD may be a single glass transition temperature (Tg).
  • Tg glass transition temperature
  • a single Tg is also evidence of a homogeneous mixture of amorphous acalabrutinib and polymer.
  • Samples as such without any further sample preparation may be used for the determination of the Tg, the determination may run for example in modulated mode at a scan rate of 2.5 °C/min, modulation of ⁇ 1.5 °C/min, and a scan range from 0 to 180 °C.
  • Amorphous nature of acalabrutinib shows a Tg which is equal to the Tg of neat DSISPPOL or which is between the Tg of the polymer and the Tg of the acalabrutinib.
  • the Tg of the ASD is often similar to the weighted average of the Tg of acalabrutinib and the Tg of DISPPOL.
  • ASDs according to the invention exhibit a single glass transition temperature as measured by DSC and disclosed herein evidencing that the ASDs according to the invention are homogeneous molecular dispersions.
  • DISPPOL may be selected from the group consisting of HPMCAS, HPMC, CAP, HPMCP, CMEC, PVA-P, polysaccharides, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, poly vinylpyrrolidone-vinyl acetate copolymers (PVPVA), C1-C6 polyalkylene glycols, copolymers of polyethylene glycol and polypropylene glycol, methacrylic Acid - methyl methacrylate copolymers, methacrylic acid - ethyl acrylate copolymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, and mixtures thereof.
  • Suitable polysaccharides include, for example, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), optionally substituted alpha-cyclodextrins, optionally substituted beta- cyclodextrins, optionally substituted gamma-cyclodextrins, and mixtures thereof.
  • HPMC hydroxypropyl methylcellulose
  • CMC carboxymethyl cellulose
  • HPC hydroxypropyl cellulose
  • optionally substituted alpha-cyclodextrins optionally substituted beta- cyclodextrins
  • optionally substituted gamma-cyclodextrins optionally substituted gamma-cyclodextrins, and mixtures thereof.
  • HPMCAS is sold under the tradename AQOAT® and AQOAT® HF by Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan).
  • Polymethacrylates include PMMA-MAA (poly(methyl methacrylate-co-methacrylic acid), e.g. Eudragit® L100 by Evonik Industries AG, Essen, Germany.
  • PVPVA is sold under the tradename Kollidon®, BASF, Ludwigshafen, Germany.
  • C1-C6 polyalkylene glycols may be polypropylene glycol or polyethylene glycol.
  • Copolymers of polyethylene glycol and polypropylene glycol may be the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC® tradename.
  • Methacrylic acid - methyl methacrylate copolymers may be methacrylic acid - methyl methacrylate copolymer (1:1) (Eudragit® L100, Evonik Corporation, Piscataway, NJ 08855, USA), methacrylic Acid - Methyl Methacrylate Copolymer (1:2) (Eudragit S100, Evonik Corporation, Piscataway, NJ 08855, USA).
  • Methacrylic acid - ethyl acrylate copolymers may be methacrylic acid - ethyl acrylate copolymers (1:1) (Eudragit L100-55, Evonik Corporation, Piscataway, NJ 08855,
  • Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer may be Soluplus®, BASF, Ludwigshafen, Germany.
  • Beta-cyclodextrins may be hydroxypropyl beta-cyclodextrin.
  • Gamma-cyclodextrins may be hydroxypropyl gamma-cyclodextrin.
  • DISPPOL is selected from the group consisting of HPMCAS, PMMA-MAA, PVPVA, PVP and HPMC or mixtures thereof.
  • DISPPOL is selected from the group consisting of HPMCAS, PVPVA, PVP and HPMC.
  • DISPPOL is HPMCAS.
  • HPMCAS may have an acetyl content of 5 to 14 wt%; the wt% based on the weight of the HPMCAS.
  • HPMCAS may have a succinoyl content of 4 to 18 wt%; the wt% based on the weight of the HPMCAS.
  • HPMCAS may have an acetyl content of 5 to 14 wt% and a succinoyl content of 4 to 18 wt%; the wt% based on the weight of the HPMCAS.
  • HPMCAS may have an acetyl content of 5 to 9 wt%, of 7 to 11 wt%, or 10 to 14 wt%; the wt% based on the weight of the HPMCAS.
  • HPMCAS may have a succinoyl content of 14 to 18 wt%, of 10 to 14 wt%, or of 4 to 8 wt%; wt% based on the weight of the HPMCAS.
  • HPMCAS may be have an acetyl content of 5 to 9 wt% and a succinoyl content of 14 to 18 wt%; an acetyl content of 7 to 11 wt% and a succinoyl content of 10 to 14 wt%; or an acetyl content of 10 to 14 wt% and a succinoyl content of 4 to 8 wt%; even more preferably, HPMCAS may be have an acetyl content of 10 to 14 wt% and a succinoyl content of 4 to 8 wt%; the wt% based on the weight of the HPMCAS.
  • HPMCAS may be one of the commercially available three different grades, grade L, grade M and grade H characterized by the contents:
  • grade L having an acetyl content of 5 to 9 wt% and a succinoyl content of 14 to 18 wt%;
  • grade M having an acetyl content of 7 to 11 wt% and a succinoyl content of 10 to 14 wt%;
  • HPMCAS may be of grade H characterized by the contents:
  • the grades of HPMCAS may be characterized by a hydroxypropoxyl content of from 5 to 10 wt%, preferably, by their hydroxypropoxyl content of from 5 to 9 wt% or of from 6 to 10 wt%; the wt% based on the weight of the HPMCAS.
  • grade L has a hydroxypropxy content of from 5 to 9 wt%
  • grade M has a hydroxypropxy content of from 5 to 9 wt%
  • grade H has a hydroxypropxy content of from 6 to 10 wt%; the wt% based on the weight of the HPMCAS.
  • HPMCAS may be characterized by the contents:
  • HPMCAS may be characterized by the contents:
  • HPMCAS • an acetyl content of 11 to 13 wt% and a succinoyl content of 5 to 7 wt% and a hydroxypropxy content of from 7 to 9 wt%; more especially, HPMCAS may be characterized by the contents:
  • the HPMCAS may be further characterized by its methoxy content of from 20 to 26 wt%; the wt% based on the weight of the HPMCAS.
  • the HPMCAS may be further characterized by its methoxy content of from 20 to 24 wt%, of from 21 to 25 wt%, or of from 22 to 26 wt%; preferably, of from 22 to 26 wt%; the wt% based on the weight of the HPMCAS.
  • grade L having an methoxy content of 20 to 24 wt%
  • grade M having an methoxy content of 21 to 25 wt%
  • HPMCAS may be of grade H characterized by the methoxy content of 22 to 26 wt%; the wt% based on the weight of the HPMCAS.
  • the HPMCAS may be further characterized by its glass transition temperature Tg of 122 °C.
  • the HPMCAS may be further characterized by its viscosity of from 2.0 to 4.0 mPa*s, preferably from 2.2 to 3.8 mPa*s, more preferably from 2.4 to 3.6 mPa*s, the viscosity being measured with a 2 w/w% solution of sodium hydroxide aqueous solution at 20 °C.
  • the ASD may comprise from 1 to 99 wt%, preferably from 10 to 95 wt%, more preferably from 10 to 80 wt%, even more preferably from 20 to 60 wt%, of acalabrutinib, the wt% being based on the weight of the ASD.
  • the ASD may comprise from 1 to 99 wt%, preferably from 5 to 90 wt%, more preferably from 20 to 90 wt%, even more preferably from 40 to 80 wt%, of DISPPOL, the wt% being based on the weight of the ASD.
  • the ASD may comprise from 1 to 99 wt% of acalabrutinib and from 1 to 99 wt% of DISPPOL, with the combined content of acalabrutinib and DISPPOL being from 2 to 100 wt%; preferably from 10 to 95 wt% of acalabrutinib and from 5 to 90 wt% of DISPPOL, with the combined content of acalabrutinib and DISPPOL being from 15 to 100 wt%; preferably from 10 to 80 wt% of acalabrutinib and from 20 to 90 wt% of DISPPOL, with the combined content of acalabrutinib and DISPPOL being from 30 to 100 wt%; more preferably from 20 to 60 wt% of acalabrutinib and from 40 to 80 wt% of DISPPOL, with the combined content of acalabrutinib and DISPPOL being from 60 to
  • the combined content of acalabrutinib and DISPPOL is from 65 to 100 wt%, more preferably from 67.5 to 100 wt%, even more preferably from 80 to 100 wt%; especially from 90 to 100 wt%; more especially from 95 to 100 wt%; the wt% being based on the weight of the ASD; especially the ASD consists of acalabrutinib and DISPPOL.
  • the ASD may comprise
  • acalabrutinib and DISPPOL • from 45 to 77.5 wt% of hydroxypropyl methylcellulose acetate succinate DISPPOL; with the combined content of acalabrutinib and DISPPOL being from 65 to 100 wt%, more preferably from 67.5 to 100 wt%, even more preferably from 80 to 100 wt%; especially from 90 to 100 wt%; more especially from 95 to 100 wt%; the wt% being based on the weight of the ASD; even more preferably the ASD consists of acalabrutinib and DISPPOL.
  • the ASD may comprise
  • acalabrutinib and DISPPOL • from 72.5 to 77.5 wt% of hydroxypropyl methylcellulose acetate succinate DISPPOL; with the combined content of acalabrutinib and DISPPOL being from 95 to 100 wt%; the wt% being based on the weight of the ASD; more preferably the ASD consists of acalabrutinib and DISPPOL.
  • the ASD may comprise
  • acalabrutinib and DISPPOL • from 45 to 55 wt% of hydroxypropyl methylcellulose acetate succinate DISPPOL; with the combined content of acalabrutinib and DISPPOL being from 90 to 100 wt%, more preferably from 95 to 100 wt%; the wt% being based on the weight of the ASD; more preferably the ASD consists of acalabrutinib and DISPPOL.
  • the ASD may comprise at least one excipient ASDEXCIP, preferably 1, 2, 3, 4 or 5 ASDEXCIP, more preferably 1, 2, 3 or 4 ASDEXCIP, even more preferably 1, 2 or 3 ASDEXCIP, especially 1 or 2 ASDEXCIP, more especially 1 ASDEXCIP.
  • the ASD may comprise ASDEXCIP in an amount up to 40 wt%, the wt% being based on the weight of the ASD.
  • the ASD consists of the acalabrutinib, the DISPPOL and said at least one ASDEXCIP.
  • ASDEXCIP may be any pharmaceutically acceptable excipient.
  • ASDEXCIP may be a surfactant, a salt, a solubilizer, a lubricant, a glidant, a filler or any combination thereof.
  • Surfactants include, for example, sulfonated hydrocarbons and their salts, including fatty acid and alkyl sulfonates, such as sodium l,4-bis(2-ethylhexyl)sulfosuccinate, also known as docusate sodium (CROPOL) and sodium lauryl sulfate (SLS); poloxamers, also referred to as polyoxyethylene-polyoxypropylene block copolymers (PLURONICs, LUTROLs); polyoxyethylene alkyl ethers (CREMOPHOR A, BRIJ, available from ICI Americas Inc., Wilmington, Del.); polyoxyethylene sorbitan fatty acid esters (polysorbates, TWEEN available from ICI); short-chain glyceryl mono-alkylates (HOD AG, IMWITTOR, MYRJ); mono- and di-alkylate esters of polyols, such as glycerol; nonionic surfactants such as polyoxy
  • Salts may be NaCl, KC1, MgCh, Mg3Citrate2, Na 3 PC>4, K3PO4, MgS04, Na3Citrate, K3Citrate, Na 2 S0 4 , or any other salt contained within a known salt form of acalabrutinib.
  • Solubilizers include polyethylene glycols, caffeine, xanthene, gentisic acid, and cyclodextrins.
  • Lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Glidants include, for example, silicon dioxide, talc, and cornstarch.
  • Fillers include lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose, powdered cellulose, fumed silica, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, and poloxamers such as polyethylene oxide.
  • ASDEXCIP examples include but are not limited to polyvinylpyrrolidone (PVP), dipalmitoyl phosphatidyl choline (DPPC), trehalose, sodium bicarbonate, glycine, and sodium citrate.
  • PVP polyvinylpyrrolidone
  • DPPC dipalmitoyl phosphatidyl choline
  • trehalose sodium bicarbonate
  • glycine glycine
  • sodium citrate sodium citrate
  • the ASD may be in the form of a powder, rod, pellet, or any form that may come from spray drying, hot melt extrusion or high shear mixing.
  • the invention further provides methods for preparation of ASDs as described herein.
  • ASD is manufactured by a process selected from the group consisting of spray drying, hot melt extrusion, coprecipitation, a non-solvent, higher shear process with a short duration of high temperature, lyophilization, rotary evaporation, or with a combination of such processes; with the ASD as defined herein, also with all its embodiment.
  • a non-solvent, higher shear process with a short duration of high temperature is known under the tradename Kinetisol®., DisperSol Technologies, Georgetown, TX 78626, US.
  • the method for preparation of the ASD is spray drying.
  • the method for preparation of the ASD is spray drying, wherein acalabrutinib and DISPPOL and optionally ASDEXCIP are dissolved in a solvent SOLV to provide a solution SOL of acalabrutinib and DISPPOL and optionally ASDEXCIP in SOLV;
  • SOL is spray dried to provide the ASD
  • SOLV is selected from the group consisting of methanol, acetone, DCM, THF, water and mixtures thereof; with DISPPOL and ASDEXCIP as defined herein, also with all its embodiments.
  • SOLV may be methanol, acetone, DCM, THF, a mixture of acetone and water, a mixture of methanol and water, a mixture of DCM and methanol or a mixture of THF and water.
  • SOLV is methanol, acetone or a mixture thereof, even more preferably SOLV is methanol or acetone, especially SOLV is methanol.
  • the combined amount of acalabrutinib and of DISPPOL in SOL may be from 1 to 15 wt%, preferably from 2 to 10 wt%, even more preferably from 2 to 8 wt%, especially from 4 to 7 wt%, the wt% being based on the total weight of SOL.
  • the relative amounts of acalabrutinib and of DISPPOL with respect to each other in SOL may be the same as the amounts of acalabrutinib and of DISPPOL relative to each other in the ASD as given herein, also with all their embodiments.
  • the amount of any ASDEXCIP in SOL is given by the desired amount of ASDEXCIP in the ASD.
  • the ASD may be a spray dried ASD.
  • the spray drying may be done with an inlet temperature of from 100 to 170 °C, preferably from 110 to 165 °C, more preferably from 120 to 165 °C, even more preferably from 130 to 160 °C.
  • the inlet temperature is from 135 to 155 °C.
  • the spray drying may be done with an outlet temperature of from 20 to 70 °C, preferably from 30 to 70 °C, more preferably from 35 to 60 °C, even more preferably from 40 to 55 °C.
  • the outlet temperature is from 45 to 50 °C.
  • Any residual solvent may be removed after spray drying by conventional drying, such as drying under vacuum; said conventional drying may be done under elevated temperature, such as from 30 to 50 °C.
  • One embodiment of the invention relates to an ASD obtainable by a method for preparation of the ASD, with the method and the ASD as defined herein, also with all their embodiments.
  • the ASD is used in form of a pharmaceutical dosage form PDF.
  • the PDF may be a solid dosage form SDF, that is a solid PDF.
  • Another subject of the invention is a pharmaceutical dosage form PDF comprising an ASD, with the ASD as defined herein, also with all its embodiments.
  • the PDF is an oral PDF.
  • PDF may be a capsule, a tablet, a sachet or a caplet.
  • said PDF is a capsule, a tablet or a caplet.
  • the PDF may comprise in addition to the ASD at least one excipient PDFEXCIP, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PDFEXCIP, more preferably 1, 2, 3, 4, 5 or 6 PDFEXCIP, even more preferably 1, 2, 3 or 4 PDFEXCIP, especially 2, 3 or 4 PDFEXCIP, more especially 3 or 4 PDFEXCIP.
  • excipient PDFEXCIP preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PDFEXCIP, more preferably 1, 2, 3, 4, 5 or 6 PDFEXCIP, even more preferably 1, 2, 3 or 4 PDFEXCIP, especially 2, 3 or 4 PDFEXCIP, more especially 3 or 4 PDFEXCIP.
  • the PDF may comprise PDFEXCIP in an amount up to 90 wt%, the wt% being based on the weight of the PDF.
  • PDFEXCIPs may be any excipients which are common in the formulation of PDFs of medicaments, for example such excipients as disclosed herein under ASDEXCIP for use in the preparation of the ASD.
  • the ASD is compressed to form the tablet or caplet;
  • PDFEXCIPs may be blended with the ASD before the compression to a tablet or to a caplet.
  • the ASD may be mixed with PDFEXCIP to form a mixture.
  • Mixing processes include physical processing, as well as granulation and coating processes.
  • Exemplary mixing methods include granulation, convective mixing, shear mixing, diffusive mixing, or milling.
  • the mixture is formed by dry granulation, wet granulation, roller compaction/milling or any combination thereof.
  • the mixture may then be then formed into the PDF.
  • the mixture is molded or compressed, as known in the pharmaceutical arts, to provide a tablet or caplet.
  • Tablets or caplets may also be produced directly by compressing a desired pharmaceutical composition comprising the ASD into a tablet or caplet form, they may also be prepared by first compacting the ASD into a roller form, with or without excipients, and then blend it with other excipients and compress it into tablet or caplet form.
  • excipients may also be filled into the capsule shell, they may be mixed with the ASD before the blend is mixed into the capsule shell, the mixing of the ASD with excipients can be done in any way as described herein.
  • excipients may be such that are conventionally used in the preparation of tablets or caplets, sachets or in the preparation of a fill of a capsule shell, they are known to the skilled person. Examples of excipients are those mentioned herein.
  • the ASD and any optional PDFEXCIP are granulated via roller compaction.
  • the ASD and any optional PDFEXCIP are blended and directly compressed to tablets without granulation (direct compression); this direct compression to tablets may be suitable for example in case of hot melt extrusion.
  • the PDF is a rapidly disintegrating PDF, in particular an immediate release tablet or an immediate release capsule.
  • the PDF is a controlled release or delayed release PDF, particularly an enteric coated tablet or capsule.
  • the PDF is a High Loaded Dosage Form (HLDF) comprising ASD and one or more concentration sustaining polymers (CSP).
  • HLDF can yield substantially reduced tablet mass while providing similar physical stability and in vitro performance as conventional dosage forms.
  • the CSP is an ionizable cellulosic polymer, a nonionizable cellulosic polymer, an ionizable non-cellulosic polymer, a non-ionizable non- cellulosic polymer, or a combination thereof.
  • the CSP is not PMMA-MAA.
  • Ionizable cellulosic polymers include hydroxypropyl methyl cellulose succinate, cellulose acetate succinate, methyl cellulose acetate succinate, ethyl cellulose acetate succinate, hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate succinate, hydroxypropyl cellulose butyrate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate,
  • Non-ionizable cellulosic polymers include hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose, and combinations thereof.
  • Ionizable non-cellulosic polymers include carboxylic acid functionalized polymethacrylates, carboxylic acid functionalized polyacrylates, amine-functionalized polyacrylates, amine- functionalized polymethacrylates, proteins, and carboxylic acid functionalized starches, and combinations thereof.
  • Non-ionizable non-cellulosic polymers include vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclicamido; vinyl copolymers of at least one hydrophilic, hydroxyl-containing repeat unit and at least one hydrophobic, alkyl- or arylcontaining repeat unit; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed form, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol polypropylene glycol copolymers, polyvinyl pyrrolidone, and polyethylene polyvinyl alcohol copolymers, and combinations thereof.
  • the CSP comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), carboxymethyl ethylcellulose (CMEC), or a combination thereof.
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • HPMC hydroxypropyl methylcellulose
  • PVPVA poly(vinylpyrrolidone-co-vinyl acetate)
  • CMEC carboxymethyl ethylcellulose
  • the CSP comprises HPMCAS or PVPVA.
  • HPMCAS may be, for example, HPMCAS-HF or Affmisol® 126 HPMCAS polymer (The Dow Chemical Company).
  • HPMCAS-HF may have an average particle size of 10 micrometer or less, such as an average particle size of 5 micrometer, as measured by laser diffraction.
  • HPMCAS-HF and Affmisol® 126 HPMCAS each may have an acetyl content of 10 to 14 wt%, a succinoyl content of 4 to 8 wt%, a methoxyl content of 22 to 26 wt%, and a hydroxypropoxy content of 6 to 10 wt%.
  • HPCMAS-HF and Affmisol® 126 HPMCAS may have an acid content of 0.7 mmol acid/gram and are soluble at pH of 6.5 or greater.
  • the PVPVA may be, for example, PVP-VA64, which is a linear random copolymer with a 6:4 ratio of N-vinylpyrrolidone and vinyl acetate.
  • PVP-VA64 is a linear random copolymer with a 6:4 ratio of N-vinylpyrrolidone and vinyl acetate.
  • a commercially available example is Kollidon® VA 64 polymer (BASF Corporation).
  • PVPVA is soluble in gastric media (e.g., at pH 2), PVPVA may retard or prevent crystallization of some active agents in gastric media.
  • One embodiment of the invention relates a PDF for use as therapeutically active substance, with the PDF as described herein, also with all its embodiments.
  • One embodiment of the invention relates to a PDF for use in the treatment or prevention of lymphoma, preferably non-Hodgkin lymphoma, more preferably mantle cell lymphoma, with the PDF as described herein, also with all its embodiments.
  • lymphoma preferably non-Hodgkin lymphoma, more preferably mantle cell lymphoma
  • One embodiment of the invention relates to the use of a PDF for the treatment or prevention of lymphoma, preferably non-Hodgkin lymphoma, more preferably mantle cell lymphoma, with the PDF as described herein, also with all its embodiments.
  • lymphoma preferably non-Hodgkin lymphoma, more preferably mantle cell lymphoma
  • One embodiment of the invention relates to the use of a PDF for the preparation of medicaments useful for the treatment or prevention of lymphoma, preferably non-Hodgkin lymphoma, more preferably mantle cell lymphoma, with the PDF as described herein, also with all its embodiments.
  • lymphoma preferably non-Hodgkin lymphoma, more preferably mantle cell lymphoma
  • One embodiment of the invention relates to a method for the treatment or prevention of lymphoma, preferably non-Hodgkin lymphoma, more preferably mantle cell lymphoma, which method comprises administering a PDF to a human being or animal, with the PDF as described herein, also with all its embodiments.
  • lymphoma preferably non-Hodgkin lymphoma, more preferably mantle cell lymphoma
  • the PDF is administered once daily, preferably once daily to a human being or animal, with the PDF as described herein, also with all its embodiments.
  • One embodiment of the invention relates to a method for the treatment or prevention of lymphoma, characterized by the sequential or concomitant administration of an ASD with a proton pump inhibitor (PPI), antacid or H2 -receptor antagonist, with the ASD as described herein, also with all its embodiments.
  • PPI proton pump inhibitor
  • One embodiment of the invention relates pharmaceutical fixed dose dosage form comprising both an ASD and a proton pump inhibitor (PPI), antacid or H2 -receptor antagonist, with the ASD as described herein, also with all its embodiments.
  • PPI proton pump inhibitor
  • One embodiment of the invention relates pharmaceutical fixed dose dosage form comprising both an ASD and a proton pump inhibitor (PPI), antacid or H2 -receptor antagonist for use in the treatment or prevention of gastroesophageal reflux disease, esophageal duodenal and stomach ulcers, NSAID-associated ulcer, Zollinger-Ellison syndrome, stress gastritis, pancreatic insufficiency, non-ulcer dyspepsia, biliary reflux, constipation, osteoporosis, urinary alkalinization, phosphate binding in chronic renal failure, with the ASD as described herein, also with all its embodiments.
  • PPI proton pump inhibitor
  • One embodiment of the invention relates to the use of a PDF comprising an ASD in a sequential or concomitant use of the PDF and a dosage form comprising a proton pump inhibitor (PPI), antacid or H2 -receptor antagonist, with the ASD and the PDF as described herein, also with all its embodiments.
  • PPI proton pump inhibitor
  • One embodiment of the invention relates to the use of a PDF comprising an ASD in a sequential or concomitant use of the PDF and a dosage form comprising a proton pump inhibitor (PPI), antacid or H2 -receptor antagonist for the treatment or prevention of gastroesophageal reflux disease, esophageal duodenal and stomach ulcers, NSAID-associated ulcer, Zollinger-Ellison syndrome, stress gastritis, pancreatic insufficiency, non-ulcer dyspepsia, biliary reflux, constipation, osteoporosis, urinary alkalinization, phosphate binding in chronic renal failure, with the ASD and the PDF as described herein, also with all its embodiments.
  • PPI proton pump inhibitor
  • H2 -receptor antagonist for the treatment or prevention of gastroesophageal reflux disease, esophageal duodenal and stomach ulcers, NSAID-associated ulcer, Zollinger-Ellison syndrome, stress gast
  • One embodiment of the invention relates to a method for the treatment of a human being or animal, which method comprises sequential or concomitant administration of a PDF comprising an ASD and a dosage form comprising a proton pump inhibitor (PPI), antacid or H2 -receptor antagonist, with the ASD and the PDF as described herein, also with all its embodiments.
  • a PDF comprising an ASD and a dosage form comprising a proton pump inhibitor (PPI), antacid or H2 -receptor antagonist
  • the proton pump inhibitor may be Omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, dexlansoprazole, or other suitable PPIs known to the skilled person.
  • the antacid may be aluminum hydroxide, calcium carbonate, magnesium hydroxide, bismuth subsalicylate, antacids in form of drugs, such as maalox, mylanta, rolaids, gaviscon, or gelusil, or other suitable antacids known to the skilled person.
  • the H2 -receptor antagonist may be cimetidine, famotidine, ranitidine, nizatidine, or other suitable H2 -receptor antagonists known to the skilled person.
  • Form I Crystalline acalabrutinib Form I is disclosed in WO 2017/002095 A1 [0087] Form I was prepared by taking the purchased acalabrutinib and recrystallizing it to obtain Form I, recrystallization was done according to WO 2017/002095 Al, Example 1, Table 1, Sample 23.
  • Verification of Form I was done by DSC to determine the melting temperature which was 210 °C, which is close to the 214 °C reported in WO 2017/002095 Al, and by matching the PXRD diffractogram of the recrystallized material to Fig .1 of WO 2017/002095 Al, which matched as illustrated in Fig 6 herein.
  • Acalabrutinib is a poorly soluble, highly permeable Biopharmaceutics Classification System (BCS) 2 drug substance.
  • Acalabrutinib Form I has the following properties: Tm 214 °C.
  • Calquence capsule acalabrutinib Form I 100 mg dosage strength with respect to acalabrutinib, Drug World, Cold Spring, NY, USA
  • FaSSIF/FeSSIF/FaSSGF Fasted-state simulated intestinal medium powder was purchased from Biorelevant.com Ltd. (London, United Kingdom).
  • HPMC E3 MethocelTM E3 LV Hydroxypropyl Methylcellulose, Manufacturer DuPont de Nemours, Inc., Wilmington, Delaware, USA
  • HPMCAS in form of AQOAT® HG also called AS-HG
  • MG also called AS-MG
  • LG also called AS-LG
  • the letters L, M, and H specify the grade and distinguish the contents of acetyl and succinoyl groups.
  • the Letter G represents granular grade with a Mean Particle Size of 1 mm
  • a letter F instead of a G would represent micronized grade with a Mean Particle Size of 5 micrometer.
  • Various contents and parameters of these grades are given in Table 3.
  • Tg of the HPMCAS was determined by DSC experiment under the following test condition:
  • Magnesium stearate purchased from Macron Fine Chemicals/ Avantor, Radnor, PA, USA
  • MeOH Methanol (HPLC grade) was purchased from Honeywell (Morris Plains, NJ, USA)
  • Pearlitol 25 Foremost ® Pearlitol 25 was purchased from Roquette America Inc., Geneva, IL 60134, USA
  • HC1 sodium acetate, sodium phosphate, potassium phosphate, and NaCl were purchased from Sigma Aldrich Chemical Company (St. Louis, Missouri, USA)
  • the SOL-25 series contained 25 wt% of acalabrutinib based on combined weight of acalabrutinib and HPMCAS, and 6 wt% of total solids (i.e weight of acalabrutinib plus weight of HPMCAS of the respective grade) based on the combined weight of acalabrutinib, HPMCAS and methanol:
  • the SOL-50 series contained 50 wt% of acalabrutinib based on combined weight of acalabrutinib and HPMCAS, and 5.4 wt% of total solids (i.e weight of acalabrutinib plus weight of HPMCAS of the respective grade) based on the combined weight of acalabrutinib, HPMCAS and methanol:
  • SOL-50 2.0 pressure-swirl nozzle with 0.20 mm diameter
  • Fig 1 shows the PXRD diffractogram of ASD-50-H which is exemplary for the other five ASDs.
  • the ASDs and acalabrutinib Form I were evaluated for dissolution performance in a gastric medium to intestinal medium transfer dissolution performance test using a MicroDissTM Profiler with RainbowTM fiber optic UV probe detection (Pion Inc., Billerca, MA, USA).
  • INTMED-5 and INTMED-6 were attained by charging an intestinal buffer INTBUFF-5 or an intestinal buffer INTBUFF-6 respectively as described herein, details are given in Table 4.
  • GASTMED-5 and GASTMED-6 represented fasted humans taking a proton pump inhibitor (PPI).
  • PPI proton pump inhibitor
  • acalabrutinib Form I or an ASD was prepared as an aqueous suspension containing 0.5 wt% Methocel A4M, the wt% based on the weight of the aqueous suspension, at a concentration of 25 mg/ml acalabrutinib, and this aqueous suspension was then used for the tests.
  • Dissolution performance in gastric medium was monitored for 30 min with Pion RainbowTM UV probes using a wavelength range of 298 to 308 nm for GASTMED- 5 or 340 to 344 nm for GASTMED-6 within a calibration range of from 0 to 0.6 mg/ml.
  • gastric medium was diluted 1 : 1 with 10 ml of the respective intestinal buffer to attain a respective final volume of 20 ml representing the respective intestinal medium and a respective concentration of 1 mg/ml acalabrutinib.
  • Dissolution performance in the intestinal medium was monitored for 160 min at 340 to 344 nm using a calibration range of 0 to 0.6 mg/ml.
  • the apparent concentrations measured consisted of (1) acalabrutinib dissolved in aqueous medium or (2) acalabrutinib partitioned into bile-salt micelles as micelle-bound drug. All samples were analyzed in duplicate.
  • AUC Area Under the Curve
  • the ASDs were stored under elevated temperature and humidity conditions to facilitate an increase in the rate of physical changes occurring in the materials and thereby to simulate a longer storage interval in a typical storage environment.
  • Approximately 180 mg of an ASD was transferred to a 4 ml scintillation vial and placed inside a 40 ml HDPE bottle.
  • Each bottle was sealed with perforated aluminum foil and transferred to a temperature- and humidity-controlled oven (Model ES2000, Bruson, Inc. of EMCOR Group, Inc., Clemmons, NC 27012, US) at 40 °C and 75 % relative humidity and allowed to stand undisturbed for 28 days.
  • the ASDs were analyzed to confirm that they were homogeneous as evidenced by a single glass transition temperature (Tg) using a TA Instruments Q2000 modulated differential scanning calorimeter (TA Instrum ents-Waters L.L.C, New Castle, DE, US). Samples as such without any further sample preparation were loaded into a Tzero pan (TA Instruments). Samples were then crimped with non-hermetic lids and were run in modulated mode at a scan rate of 2.5 °C/min, modulation of ⁇ 1.5 °C/min, and a scan range 0 to 180 °C.
  • Fig 9 shows the DSC thermograms of 4 different ASDs ASD-25-M, ASD-25-H, ASD-50-H, and ASD-50-M.They show the amorphous nature of the ASDs and are exemplary for the other ASDs.
  • the ASDs were visually assessed with SEM for the presence of crystals and changes in particle appearance such as shape and morphology, before and after exposure to increased temperature and humidity.
  • Approximately 0.5 mg of sample was mounted to an aluminum stub with 2-sided carbon tape.
  • the sample was sputter-coated (Hummer Sputtering System, Model 6.2, Anatech Ltd., SYSTEMS DIVISION - Anatech USA, Hayward, CA) with an Au/Pd stage for 10 minutes at 15 mV and studied by SEM.
  • Samples before aging generally appear as spheres or collapsed spheres with smooth and rounded faces and surfaces. Changes in particle appearance indicating physical instability include: fusing together of individual particles, changes in surface texture, changes in general particle shape, and appearance of straight edges in the particle indicating possible crystallinity.
  • Powder X-Ray Diffraction The ASDs were analyzed using PXRD to confirm they were amorphous, as evidenced by the lack of sharp Bragg diffraction peaks in the x-ray pattern, using a Rigaku MiniFlex 600 benchtop x-ray diffractometer (RIGAKU ANALYTICAL DEVICES, INC., Wilmington, MA, US) equipped with a Cu-Kalpha source and set in modified parallel beam geometry between 3 and 40° 2Theta° The scan rate was set to 2°/min with a 0.0° step size.
  • ASDs were evaluated with the Dissolution Performance Test. For the two tests with a pH 5.0 or pH 6.0 gastric medium (representative of fasted humans taking a PPI), ASDs achieve a higher maximum concentration reached in intestinal buffer and intestinal AUC.
  • Fig 2 and Fig 3 show for the transition from pH 5.0 to pH 6.5 that all ASDs perform better than Form I, and that ASD-25-H and ASD-50-H perform better than the ASD with grade M or L.
  • Fig 4 and Fig 5 show for the transition from pH 6.0 to pH 6.5 that all ASDs perform better than Form I, and that ASD-25-H and ASD-50-H perform better than the ASD with grade M or L.
  • ASDs were subjected to Accelerated Physical Stability Studies. The results demonstrated that all ASDs remained stable, i.e., the acalabrutinib remained amorphous for at least the 28-day storage period. This stability was indicated by
  • Tg values for ASDs before and after storage were within 1 °C on average as shown in Table 2.
  • Tg glass transition temperature (dry) shown as average ⁇ standard deviation
  • ASD tablet manufacturing Tablets were made using a small scale, semimanual manufacturing process.
  • the ASD and all intragranular ingredients excluding magnesium stearate were blended in a Turbula blender (GlenMills, Clifton NJ, USA) for 15 minutes at 32 rpm.
  • Magnesium stearate was added to the blender and the mixture was blended for 4 minutes at 32 rpm, providing an intragranular blend.
  • the intragranular blend was compressed into slugs using a Manesty F3 single-station tablet press (Manesty Ltd., Knowsley, England) equipped with 1 ⁇ 2 inch flat faced tooling.
  • the compression pressure was adjusted to achieve tensile strengths between 0.5 and 0.7 MPa.
  • Tensile strength was calculated using equation SI, where TS is tensile strength, F is the breaking force, D is the tablet diameter, and H is the tablet thickness. Breaking force was determined using a Schleuniger hardness tester (Sotax, Westborough, MA, USA).
  • An ASD tablet 100 mg dosage strength with respect to acalabrutinib
  • Calquence capsule 100 mg dosage strength with respect to acalabrutinib
  • the dissolved concentration was monitored with Pion RainbowTM fiber optic UV probe detection (Pion Inc., Billerca, MA, USA).
  • INTMED-6-2 and INTMED-2 were attained by charging an intestinal buffer INTBUFF-5 as described herein, details are given in Table 4 for INTBUFF-5 and Table 6 for GASTMED-2 and GASTMED-6-2.
  • GASTMED-6-2 represented fasted humans taking a proton pump inhibitor (PPI) and GASTMED-2 represented fasted humans.
  • PPI proton pump inhibitor
  • the Calquence capsule was housed inside a hanging basket located approximately 0.2 mm above the paddle of the USP-2 device.
  • the hanging basket ensured that the Calquence capsule remained submerged throughout the duration of the test.
  • the ASD tablets were dosed directly into the dissolution medium.
  • Dissolution performance in gastric medium was monitored for 30 min with Pion RainbowTM UV probes using a wavelength range of 370 to 380 nm for GASTMED-2 and GASTMED-6-2 within a calibration range of from 0 to 0.4 mg/ml.
  • gastric medium was diluted 1:1 with 250 ml of INTBUFF-5 to attain a respective final volume of 500 ml representing the respective intestinal medium INTMED-6-2 and INTMED-2 and a respective maximum concentration of 0.2 mg/ml acalabrutinib.
  • Dissolution performance in the intestinal medium was monitored for 160 min at 330 to 340 nm using a calibration range of 0 to 0.2 mg/ml.
  • the apparent concentrations measured consisted of (1) acalabrutinib dissolved in aqueous medium or (2) acalabrutinib partitioned into bile-salt micelles as micelle-bound drug. All samples were analyzed in duplicate. Analyzed was the % of dose released at 120 min. The term “% of dose” means "% of maximum possible value of 0.2 mg/ml, so the possible maximum concentration of 0.2 mg/ml equal to 100%.
  • the ASD tablet achieved a higher maximum concentration after 120 min compared to the Calquence capsule.
  • Fig 7 shows for the transition from pH 2.0 to pH 6.5 that the ASD tablet performs comparable to Calquence capsule.
  • Fig 2 shows for the transition from pH 6.0 to pH 6.5 that the ASD tablet performs better than Calquence capsule.
  • Acalabrutinib and the polymer were dissolved in a solvent of either methanol or 9/1 methanol/water (w/w) to provide the solutions series SOL-50-K30, SOL-50-VA64 and SOL- 50-E3:
  • This SOL-50 series contained 50 wt% of acalabrutinib based on combined weight of acalabrutinib and polymer, and either 3.3 wt% or 5.4 wt% of total solids (i.e weight of acalabrutinib plus weight of polymer) based on the combined weight of acalabrutinib, polymer and the solvent:
  • the solutions were spray dried with an outlet temperature of 40 to 50 °C and an inlet temperature of 130 to 155 °C on a custom-made laboratory scale spray dryer with a 35 kg/h drying gas (nitrogen) flow and a 0.3 m chamber diameter.
  • Nozzles used 2.0 pressure-swirl nozzle with 0.20 mm diameter; SCHLICK Hollow-Cone, model 121 with normal spray cone, Schlick Americas, Bluffton, South Carolina, USA.
  • SOL-50-E3 provided ASD-50-E3 All 3 ASDs were analyzed by PXRD and showed amorphous nature;
  • Fig 1 shows the PXRD diffractogram of ASD-50-H which is exemplary also for ASD-50-K30, ASD-50-VA64 and ASD-50-E3. Dissolution Performance Test
  • the ASDs and acalabrutinib Form I were evaluated for dissolution performance in a gastric medium to intestinal medium transfer dissolution performance test using a MicroDissTM Profiler with RainbowTM fiber optic UV probe detection (Pion Inc., Billerca, MA, USA).
  • a gastric to intestinal transfer dissolution performance test was done.
  • Acalabrutinib in its respective form was exposed to a gastric medium GASTMED-6 first and then exposed to an intestinal medium INTMED-6.
  • INTMED-6 was attained by charging an intestinal buffer INTBUFF-6 as described herein, details are given in Table 8.
  • GASTMED-6 represented fasted humans taking a proton pump inhibitor (PPI).
  • PPI proton pump inhibitor
  • Dissolution performance in gastric medium was monitored for 30 min with Pion RainbowTM UV probes using a wavelength range of 340 to 350 nm for GASTMED- 6 within a calibration range of from 0 to 0.6 mg/ml.
  • gastric medium was diluted 1 : 1 with 10 ml of the intestinal buffer to attain a respective final volume of 20 ml representing the respective intestinal medium and a respective concentration of 1.5 mg/ml acalabrutinib.
  • Dissolution performance in the intestinal medium was monitored for 150 min at 340 to 344 nm using a calibration range of 0 to 0.7 mg/ml.
  • ASDs were evaluated with the Dissolution Performance Test. For the test with a pH 6.0 gastric medium (representative of fasted humans taking a PPI), ASD-50-K30 achieved a higher maximum concentration reached in intestinal buffer and intestinal AUC compared to acalabrutinib Form I.
  • ASD-50-VA64 and ASD-50-E3 also achieve a higher maximum concentration reached in intestinal buffer and intestinal AUC compared to acalabrutinib Form T
  • the results in form of the values of AUC ratio AUC(ASD)/AUC(acalabrutinib Form I) are shown in Table 9. The results are illustrated also in Fig 10, Fig 14 and Fig 15:
  • Fig 10 shows for the transition from pH 6.0 to pH 6.5 that ASD-50-K30 performed better than Form F
  • Fig 14 and Fig 15 show for the transition from pH 6.0 to pH 6.5 that ASD-50-VA64 and ASD-50-E3 performed better than Form F Better performance means high concentration at a given point of time.
  • ASD-50-K30 was subjected to Accelerated Physical Stability Studies for 28 days. The results demonstrated that the ASD remained amorphous by PXRD (the PXRD diffractogram didn't show any change after 28 days), but phase separated as evident by two distinct T g by DSC.
  • the dry T g of PVP-K30 is ca. 157 °C, suggesting that one of the measured transitions is a polymer rich phase (measured T g of 154 °C). This is illustrated in Fig 11.
  • Tg glass transition temperature (dry) shown as average ⁇ standard deviation
  • Example 5 Polymer screening test for acalabrutinib
  • a polymer screening test using seven different polymers was performed using a solvent shift method to show the polymer’s ability to sustain acalabrutinib supersaturated drug concentrations.
  • the polymers tested included HPMCAS-H, HPMCAS-M, HPMCAS-L, Eudragit L100, HPMC E3, PVP K30 and PVP-VA64.
  • a 20 mg/ml acalabrutinib stock solution (95/5 (w/w) THF/water) was delivered into an aqueous buffer containing 200 microgram/ml of a dissolved polymer using a calibrated pipette.
  • a total of 200 microliter stock solution was added to achieve a target final concentration of 400 microgram/ml acalabrutinib.
  • the aqueous buffer composition is shown in Table 11.
  • HPMCAS-H and HPMCAS-M show the longest sustainment of supersaturation from the polymers tested (>16 h) as shown in Fig 12 (dissolved acalabrutinib as a function of time in the presence of different polymers, concentration versus time), Fig 13 (scattering as a function of time showing the onset of precipitation in the presence of different polymers, scattering versus time) and Table 12 (time to precipitation showing HPMCAS-M and HPMCAS-H preventing precipitation past 16 h).
  • the ASD tablet (100 mg dosage strength with respect to acalabrutinib) and Calquence capsule (100 mg dosage strength with respect to acalabrutinib) were evaluated for dissolution performance in a gastric medium to intestinal medium transfer dissolution performance test using a three compartment dissolution apparatus containing artificial stomach-duodenum- jejunum compartments (Lonza Ltd, Bend, Oregon, USA).
  • a schematic of the apparatus is shown in Fig 16
  • the dissolved concentration was monitored with RainbowTM fiber optic UV probe detection (Pion Inc., Billerca, MA, USA). Two different gastric to intestinal transfer dissolution performance tests were done.
  • acalabrutinib in its respective form was exposed to a gastric medium GASTMEDEX6-6 first and then exposed to an intestinal medium INTMEDEX6-6; in the other test acalabrutinib in its respective form was exposed to a gastric medium GASTMEDEX6-2 first and then exposed to an intestinal medium INTMEDEX6-2.
  • INTMEDEX6-2 and INTMEDEX6-6 were attained by charging an intestinal buffer INTBUFFEX6 as described herein, details are given in Table 13.
  • GASTMEDEX6-6 represented fasted humans taking a proton pump inhibitor (PPI) and GASTMEDEX6-2 represented fasted humans.
  • PPI proton pump inhibitor
  • GASTMEDEX6-2 represented fasted humans.
  • unique calibration curves were built for each UV probe (1 mm path length) by delivering aliquots of a known amount of stock acalabrutinib solution (20 mg/ml acalabrutinib in 95/5 w/w THF/H2O) to 50 ml of gastric medium or intestinal medium held at 37 ⁇ 2 °C.
  • the test conditions for the two gastric to intestinal transfer tests are tabulated in Table 14.
  • the Calquence capsule was housed inside a sinker basket. The sinker ensured that the capsule remained submerged throughout the duration of the disintegration period.
  • the ASD tablets were dosed directly into the dissolution medium.
  • the Calquence capsule were allowed 5 minutes of disintegration and the ASD tablet were allowed 1 minute of disintegration.
  • the transfer of fluids between the gastric-duodenum and duodenum -jejunum were maintained using two NE-9000B peristaltic pumps (New Era Systems, Farmingdale, NY, USA).
  • the gastric-duodenum emptying was programmed using SyringePumpPro software to follow an exponential first order function with a half-life of 15 min (40 steps per program).
  • the duodenum -jejunum emptying was programmed to maintain a constant 50 mL volume while accounting for the varying gastric-duodenum emptying rates and constant secretion rates.
  • the gastric and intestinal secretions were maintained using a NE-1600 syringe pump hosting four 120 mL catheter syringes (New Era Pump Systems, Farmingdale, NY, USA). Two syringes were filled with 120 mL of GASTMEDEX6-2 or GASTMEDEX6-6 respectively and two were filled with 120 mL of INTBUFFEX6. The syringes were then set to secrete 110 mL at 1.2 mL/min (to achieve a 2.4 mL/min gastric and intestinal secretion rate). Care was taken to ensure all of the lines connecting the various compartments were primed with their respective media prior to the initiation of the dissolution test.
  • the jejunum compartment was agitated using a cylindrical stir bar (1 mm in diameter, 4 mm long) set to stir at ca. 150 RPM using an IKA Mini MR stir plate (IKA-Werke GmbH, Staufen, Germany).
  • the dissolution vessels were held at 37 ⁇ 2 °C by circulating water through a heating block mounted to a water bath.
  • Dissolution performance in the gastric compartment was monitored for 90 min with Pion RainbowTM UV probes using a wavelength range of 280 nm for GASTMEDEX6-6 and 350 nm for GASTMEDEX6-2 within a calibration range of from 0 to 0.6 mg/ml.
  • Dissolution performance in the duodenum and jejunum compartments was monitored for 90 min at 280 nm using a calibration range of 0 to 0.6 mg/ml.
  • the apparent concentrations measured consisted of (1) acalabrutinib dissolved in aqueous medium or (2) acalabrutinib partitioned into bile-salt micelles as micelle-bound drug. All samples were analyzed in duplicate. Analyzed was the duodenum AUC after 90 minutes of dissolution. Each sample was tested 2 times, reported are the values and their average. AUC was calculated using the rectangular rule with 0.25 min increments between 0 and 87 minutes of the dissolution test.
  • Fig 17 shows for the stomach compartment from GASTMEDEX-2 that the ASD tablet performs identically to Calquence.
  • Fig 18 shows for the duodenum compartment from GASTMEDEX-2 that the ASD tablet performs identically to Calquence.
  • Fig 19 shows for the stomach compartment from GASTMEDEX-6 that the ASD tablet performs better than Calquence.
  • Fig 20 shows for the duodenum compartment from GASTMEDEX-6 that the ASD tablet performs better than Calquence.
  • the ASD tablet (100 mg dosage strength with respect to acalabrutinib) and Calquence capsule
  • Example 3 (100 mg dosage strength with respect to acalabrutinib) were evaluated for in vivo performance in beagle dogs.
  • the tablets were prepared as according to Example 3, "ASD tablet manufacturing”.
  • Purebred beagle dogs used in the study weighed 8.9 to 10.7 kg and were 1 to 2 years in age. For each phase, animals were fasted overnight prior to dose administration. Food was returned to the animals at approximately 4 h postdose. For each phase, a flush with approximately 10 mL water was administered to facilitate swallowing of the tablet or capsule dose form.
  • LC-MS/MS liquid chromatography/mass spectrometry
  • Acalabrutinib concentrations in dog plasma were measured using LC-MS/MS (Sciex API- 5000, Framingham, Massachusetts, USA) equipped with a positive ionization Turbo Ionspray.
  • the samples were quantitated using a linear calibration curve that was prepared by diluting a stock solution of acalabrutinib in dimethylformamide at a concentration of 20000 ng/mL.
  • the stock solution was diluted to a range of 1 to 1000 ng/mL in 1 : 1 acetonitrile: water and spiked with blank protein.
  • an internal standard was used to ensure system suitability consisting of Labetalol dissolved at 200 ng/mL in acetonitrile.
  • the dog plasma samples were prepared for analysis by precipitating the protein in acetonitrile in a 96-well plate and diluting the supernatant in 1 equivalent of acetonitrile.
  • HPLC analysis was conducted using a Phenomenex Luna Cl 8(2) HST column (dimensions: 50 mm x 2 mm, 2.5 micrometer pores) and a flow rate of 0.6 mL/min.
  • the mobile phases consisted of 15 mM ammonium formate in water containing 0.1 % formic acid and 0.1 % formic acid in acetonitrile.
  • the column temperature was maintained at 50 °C while the sample compartment was maintained at 5 °C during analysis.
  • Pharmacokinetic parameters including the C max of acalabrutinib, time to maximum plasma concentration (Tma x ), and the AUC extrapolated to infinity (AUCo-in f ) were determined for each individual subject.
  • AUCm f was calculated using a linear trapezoidal method. Results of each individual subject were averaged to obtain the reported averages and standard deviations.
  • AUCo-in f , Cma x and T m a x ratios were calculated for ASD tablets and Calquence capsules.
  • AUC of ASD tablets and Calquence capsules relative to Calquence capsules after pentagastrin pretreatment as well as statistical p-values using a one way ANOVA for AUC relative to Calquence after famotidine and Calquence after pentagastrin were calculated.
  • Calquence capsules achieved significantly reduced AUCo-i nf and C max after famotidine pretreatment compared to pentagastrin pretreatment as demonstrated by AUC and C max ratios much less than unity and a p-value ⁇ 0.05 for AUC compared to Calquence + pentagastrin.
  • ASD tablets achieved similar AUCo-i nf after famotidine and pentagastrin pretreatment compared to Calquence after pentagastrin pretreatment as represented by AUC relative to Calquence + pentagastrin close to unity, and p-values much greater than 0.05 for AUC compared to Calquence + pentagastrin.
  • Table 17 and table 18 show the results.
  • CAL in table 18 means calquence
  • FAM in table 18 means famotidine.
  • PEN in table 18 means pentagastrine.
  • Fig 21 shows acalabrutinib plasmas concentration versus time. Error bars represent standard deviation.

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  • Pharmacology & Pharmacy (AREA)
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  • Medicinal Chemistry (AREA)
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Abstract

La présente invention divulgue des dispersions solides amorphes (ASD) comprenant de l'acalabrutinib et du HPMCAS, des formes pharmaceutiques orales comprenant lesdites ASD, telles que des capsules, des comprimés ou des comprimés-capsules et un procédé de préparation desdites ASD.
PCT/EP2021/064235 2020-05-29 2021-05-27 Dispersion solide amorphe d'acalabrutinib WO2021239893A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2017002095A1 (fr) 2015-07-02 2017-01-05 Acerta Pharma B.V. Formes solides et formulations de (s)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-n-(pyridin-2-yl)benzamide

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FDA: "Highlights of prescribing information: Calquence (acalabrutinib) capsules for oral use", 1 January 2017 (2017-01-01), XP055759173, Retrieved from the Internet <URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210259s006s007lbl.pdf> [retrieved on 20201211] *
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