[go: up one dir, main page]

WO2025125565A1 - Tablet comprising enzalutamide - Google Patents

Tablet comprising enzalutamide Download PDF

Info

Publication number
WO2025125565A1
WO2025125565A1 PCT/EP2024/086209 EP2024086209W WO2025125565A1 WO 2025125565 A1 WO2025125565 A1 WO 2025125565A1 EP 2024086209 W EP2024086209 W EP 2024086209W WO 2025125565 A1 WO2025125565 A1 WO 2025125565A1
Authority
WO
WIPO (PCT)
Prior art keywords
tablet
enzalutamide
carrier
extragranular
enhancing polymer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/086209
Other languages
French (fr)
Inventor
Jernej Zadnik
David ZUPANČIČ
Anka HOTKO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KRKA dd
Original Assignee
KRKA dd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KRKA dd filed Critical KRKA dd
Publication of WO2025125565A1 publication Critical patent/WO2025125565A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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

Definitions

  • the present invention relates to tablets comprising enzalutamide and processes for its preparation including fluid bed granulation.
  • Enzalutamide chemical name 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2- sulfanylideneimidazolidin-l-yl]-2-fluoro-N-methylbenzamide, was first disclosed in WO 2006/124118. It is an androgen receptor signalling inhibitor and it is indicated for the treatment of castration-resistant prostate cancer. Enzalutamide has low solubility and high permeability and is classified as BCS class II compound.
  • Polymorphic form A of enzalutamide and a process for preparing the crystalline form A are disclosed in WO 2014/043208 and WO 2016/194813.
  • Enzalutamide commercial products are available in a form of a soft capsule or a film coated tablet.
  • the film coated tablet comprises spray dried solid dispersion of enzalutamide and polymer HPMC-AS, as described in WO 2014/043208.
  • WO 2014/043208 describes amorphous solid dispersions with numerous concentration enhancing polymers and several methods for their preparation. The most preferred are solid dispersions with HPMC-AS prepared by spray drying.
  • WO 2014/167428 describes enzalutamide solid dispersions with several polymers prepared by drying a solution of enzalutamide and polymer by distillation under reduced pressure.
  • WO 2015/118015 describes enzalutamide adsorbates comprising a surfactant and enzalutamide solid dispersions with polymers and a surfactant on a carrier.
  • Preferred polymers are HPMC or HPMC-AS.
  • WO 2018/199282 describes enzalutamide solid dispersions with PVA.
  • CN 109432016 describes ternary solid dispersions comprising enzalutamide, HPMC-AS and a third component, selected from trehalose, maltitol, cyclodextrin and Dowfax 21 A.
  • WO 2021/064123 describes a granulate consisting of enzalutamide solid dispersions with a cellulosic concentration enhancing polymer on a carrier.
  • Preferred polymers are HPMC-AS and HPMCP.
  • Granulate is prepared by fluid bed granulation by equipment commonly used.
  • WO 2021/240206 describes enzalutamide solid dispersions with at least one anionic polymer and/or at least one non-ionic polymer. Solid dispersions might be prepared by spray drying, fluid bed granulation or evaporation.
  • HPMC-AS is a polymer for preparing solid dispersions and the most efficient technique is spray drying.
  • spray drying requires expensive equipment and the process of spray drying is extremely time consuming.
  • Solid dispersions can be prepared by equipment commonly used in pharmaceutical industry, e.g. fluid bed granulator. However, we have discovered that tablets comprising a granulate of enzalutamide solid dispersion with HPMC-AS prepared by fluid bed granulation method are susceptible to crushing during handling.
  • a tablet composition comprising granules, characterized in that granules comprise a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier, wherein a concentration enhancing polymer is selected from cellulose acetate phthalate, methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate or hydroxypropyl methyl cellulose acetate succinate, preferably a concentration enhancing polymer is cellulose acetate phthalate or hydroxypropyl methyl cellulose acetate succinate, more preferably a concentration enhancing polymer is cellulose acetate phthalate.
  • composition according to any one of items (1) to (34), wherein the granules further comprise disintegrant, preferably selected from sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, preferably sodium croscarmellose.
  • disintegrant preferably selected from sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, preferably sodium croscarmellose.
  • a surfactant preferably selected from sodium lauryl sulphate or poloxamer, preferably sodium lauryl sulphate.
  • the extragranular fdler is selected from lactose, mannitol, sorbitol, sucrose, maltitol, starches, dextrose, calcium phosphates, sodium or calcium carbonates, microcrystalline cellulose, preferably microcrystalline cellulose or lactose, more preferably microcrystalline cellulose.
  • a process of preparing the tablet composition according to any one of items (1) to (50) comprising the following steps: a) Dissolving or suspending enzalutamide, the concentration enhancing polymer and optionally glidant and/or surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; b) Spraying the granulation liquid obtained in step a) on the carrier to obtain granules, preferably in fluid bed granulator; c) Drying the granules obtained in step b); d) Optionally, sieving the dried granulate obtained in step c); e) Adding extragranular excipients to dry granules obtained in step d); f) Homogenizing the mixture obtained in step e); g) Compressing the mixture obtained in step f) into tablets; h) Optionally, coating the tablets obtained in step g) with a fdm-coating.
  • a process of preparing the tablet composition according to any one of items (1) to (50) comprising the following steps: a) Dissolving or suspending enzalutamide, the concentration enhancing polymer and optionally glidant and/or surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; b) Spraying the granulation liquid obtained in step a) on the carrier, intragranular disintegrant and optionally surfactant to obtain granules, preferably in fluid bed granulator; c) Drying the granules obtained in step b); d) Optionally, sieving the dried granulate obtained in step c); e) Adding extragranular excipients to dry granules obtained in step d); f) Homogenizing the mixture obtained in step e); g) Compressing the mixture obtained in step f) into tablets; h) Optionally, coating the tablets obtained in step g) with
  • step b) is performed in fluid bed granulator.
  • a preferred embodiment is directed to a tablet composition
  • granules comprising granules, characterized in that (the) granules comprise a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier, wherein (the) concentration enhancing polymer is selected from cellulose acetate phthalate, methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, preferably cellulose acetate phthalate or hydroxypropyl methyl cellulose acetate succinate, more preferably cellulose acetate phthalate.
  • Figure 1 illustrates an X-ray powder diffraction (XRPD) pattern of Tablet 1C prepared according to Example 1 in comparison to XRPD of enzalutamide Form A.
  • XRPD X-ray powder diffraction
  • Figure 2 illustrates an X-ray powder diffraction (XRPD) pattern of Tablet 3C prepared according to Example 3 in comparison to XRPD of enzalutamide Form A.
  • XRPD X-ray powder diffraction
  • One aspect of the present invention is a tablet composition comprising granules, characterized in that granules comprise a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier.
  • the solid dispersion should be of an amorphous type.
  • the tablet composition of the present invention can be a tablet composition comprising granules, characterized in that granules comprise an amorphous solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier.
  • amorphous means a non-crystalline state that lacks the long-range order which is characteristic of a crystal.
  • a completely amorphous material neither shows XRPD diffractions nor does it show thermal events during DSC analysis.
  • Amorphous materials can be characterized by a complete disorder as well as a short-range order.
  • Amorphous solids lack long- range orientational and positional atomic or molecular order (and corresponding symmetry operators), but usually exhibit some degree of short-range orientational and/or positional order.
  • Amorphous solids can be regarded as frozen liquids: at the molecular level the structure is liquid like, while at the macroscopic level, they have viscosities and hardness typical for solids.
  • concentration enhancing polymer may be used any polymer that is able to form a solid dispersion with enzalutamide, wherein enzalutamide is in amorphous form. In this way a bioavailability of enzalutamide is increased.
  • Preferred polymers are appropriate for preparing solid dispersion with enzalutamide by using fluid-bed granulation technique.
  • the concentration enhancing polymer may be selected from cellulosic or non-cellulosic polymers.
  • Cellulosic polymers may be neutral or ionizable in water.
  • the cellulosic concentration enhancing polymer may be selected from hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxy
  • the non-cellulosic concentration enhancing polymer may selected from polyvinyl alcohol, polyvinyl pyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate), polyethyleneoxide, polyoxyethylene alkyl ethers, polymethacrylates, acrylate and methacrylate copolymers, e.g. methacrylic acid - ethyl acrylate copolymer (1: 1), graft copolymers of polyethyleneglycol, polyvinylcaprolactam and polyvinylacetate.
  • the concentration enhancing polymer is selected from cellulose acetate phthalate (CAP), methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate (HPMCP) or hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).
  • CAP cellulose acetate phthalate
  • HPMC-AS hydroxypropyl methyl cellulose acetate succinate
  • the concentration enhancing polymer is cellulose acetate phthalate (CAP) or hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).
  • the concentration enhancing polymer is hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).
  • HPMC-AS is available in several grades.
  • Preferable grade for preparing the solid dispersion of enzalutamide and the concentration enhancing polymer on a carrier is grade MG.
  • the concentration enhancing polymer is cellulose acetate phthalate (CAP).
  • CAP is a derivative of cellulose where part of the hydroxyl groups is esterized with acetic or phthalic acid. Consequently, it is not soluble in acidic media, whereas it dissolves in neutral and alkali media. Therefore, the polymer is often used also for gastro-resistant coatings of tablets. When coating is not coherent or thick enough, or when it is dispersed along the tablet it does not necessarily react as gastro resistant, i.e. the drug can be dissolved also in lower pH media.
  • the carrier may be water soluble or water insoluble, for example microcrystalline cellulose, lactose, mannitol or isomalt. Lactose can be in particular lactose monohydrate.
  • the carrier is selected from microcrystalline cellulose, lactose, mannitol or isomalt, preferably the carrier is microcrystalline cellulose or lactose.
  • Microcrystalline cellulose and lactose are widely used in oral pharmaceutical products. Both excipients are available in various types regarding physical properties, such as particle size, bulk density, flowability, moisture content. The type can be chosen regarding the suitability for the technological process, for example direct compression, dry or wet granulation, capsulating. Most often microcrystalline cellulose and lactose are used as a filler, while in our case they are used also as a carrier in fluid bed granulation.
  • Lactose is water soluble pharmaceutical excipient and thus enables faster dissolution of the tablet. Furthermore, we surprisingly found out that lactose shows better processability over microcrystalline cellulose when using fluid-bed granulation method.
  • the carrier is lactose.
  • the weight ratio of enzalutamide to the concentration enhancing polymer is from about 1: 1 to about 1:6, preferably from about 1: 1 to about 1:5, more preferably from about 1: 1.5 to about 1:4.
  • the weight ratio of enzalutamide to the concentration enhancing polymer is from about 1:2 to about 1:5, preferably from about 1:2 to about 1:4, more preferably from about 1:3 to about 1:4, even more preferably about 1:3 or about 1:4.
  • the weight ratio of enzalutamide to the concentration enhancing polymer is about 1: 1.5 or about 1:2 or about 1:3 or about 1:4, most preferably 1:4.
  • the weight ratio of enzalutamide to CAP is about 1: 1.5 or about 1:2 or about 1:3 or about 1:4, most preferably 1:4.
  • the weight ratio of enzalutamide to HPMC-AS is from about 1:2 to about 1:5, preferably from about 1:2 to about 1:4, more preferably from about 1:3 to about 1:4, even more preferably about 1:3 or about 1:4, most preferably 1:4.
  • the weight ratio of enzalutamide to the carrier is from about 1: 1 to about 1:6, preferably from about 1:2 to about 1:5, more preferably from about 1:3 to about 1:4.5, even more preferably from about 1:3 to about 1:4, most preferably from about 1:3.5 to about 1:4.
  • the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about L L l to about 1:6:6, preferably from about 1: 1.5:2 to about 1:5:5, more preferably from about 1: 1.5:3 to about 1:4:4.5, even more preferably from about 1:2:3 to about 1:4:4, most preferably from about 1:3:3.5 to about 1:4:4.
  • the concentration enhancing polymer is CAP.
  • the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1: 1.5:2 to about 1: 1.5:5, preferably from about 1: 1.5:3 to about 1: 1.5:4.5, more preferably from about 1: 1.5:3 to about 1: 1.5:4, most preferably from about 1: 1.5:3.5 to about 1: 1.5:4.
  • the concentration enhancing polymer is CAP.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1:2:2 to about 1: 1.5:5, preferably from about 1:2:3 to about 1:2:4.5, more preferably from about 1:2:3 to about 1:2:4, most preferably from about 1:2:3.5 to about 1:2:4.
  • the concentration enhancing polymer is CAP.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1:3:2 to about 1:3:5, preferably from about 1:3:3 to about 1:3:4.5, more preferably from about 1:3:3 to about 1:3:4, most preferably from about 1:3:3.5 to about 1:3:4.
  • the concentration enhancing polymer is CAP or HPMC-AS.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1:4:2 to about 1:4:5, preferably from about 1:4:3 to about 1:4:4.5, more preferably from about 1:4:3 to about 1:4:4, most preferably from about 1:4:3.5 to about 1:4:4.
  • the concentration enhancing polymer is CAP or HPMC-AS.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the tablet comprises 2-50 wt% of enzalutamide, preferably 5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8-12 wt% of enzalutamide relative to the total weight of the tablet.
  • the tablet comprises 40 mg, 80 mg, 120 mg or 160 mg of enzalutamide, preferably 40 mg or 80 mg of enzalutamide.
  • the tablet can comprise 40 mg to 160 mg of enzalutamide, preferably 40 mg to 80 mg of enzalutamide.
  • the tablet comprises:
  • the tablet comprises:
  • the tablet comprises 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet.
  • the tablet comprises:
  • the carrier 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet.
  • the tablet comprises:
  • the concentration enhancing polymer relative to the total weight of the tablet; and 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet.
  • the tablet comprises:
  • concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is in the range of about 1 : 1.5 to about 1 :2, or is about 1 : 1.5 or about 1:2.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the tablet comprises:
  • concentration enhancing polymer 25-35 wt% of the concentration enhancing polymer relative to the total weight of the tablet; wherein the concentration enhancing polymer is CAP or HPMC-AS and the weight ratio of enzalutamide to CAP or HPMC-AS is about 1:3.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the tablet comprises:
  • concentration enhancing polymer 30-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet, wherein the concentration enhancing polymer is CAP or HPMC-AS and the weight ratio of enzalutamide to CAP or HPMC-AS is about 1:4.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the tablet comprises:
  • the concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is in the range of about 1 : 1.5 to about 1 :2, or is about 1 : 1.5 or about 1:2.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the tablet comprises:
  • the concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is about 1:3.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the tablet comprises:
  • concentration enhancing polymer is HPMC-AS and the weight ratio of enzalutamide to HPMC- AS is about 1:3.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the tablet comprises:
  • concentration enhancing polymer relative to the total weight of the tablet; and 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet.
  • concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is about 1:4.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the tablet comprises:
  • concentration enhancing polymer relative to the total weight of the tablet; and 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet.
  • concentration enhancing polymer is HPMC-AS and the weight ratio of enzalutamide to HPMC- AS is about 1:4.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the solid dispersion of enzalutamide and the concentration enhancing polymer on a carrier may further comprise a glidant and/or surfactant.
  • the solid dispersion of enzalutamide and the concentration enhancing polymer on a carrier further comprises a glidant, preferably silicon dioxide.
  • the amount of the glidant included in the solid dispersion is 0.1-10 wt% preferably 0.3-5 wt%, more preferably 0.5-3 wt% relative to the total weight of the tablet.
  • the surfactant may improve a wettability of enzalutamide during granulation process and improve a dissolution of the tablet.
  • the surfactant may be selected from the group of anionic, cationic or non-ionic surfactants e.g. lecithin, sodium lauryl sulphate, phospholipids, poloxamers.
  • the solid dispersion of enzalutamide and the concentration enhancing polymer on a carrier further comprises a surfactant, preferably selected from sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
  • the amount of the surfactant included in the solid dispersion is 0.1-10 wt% preferably 0.5-5 wt%, more preferably 0.5-3 wt% relative to the total weight of the tablet.
  • a disintegrant may be added to a granulation mixture.
  • the disintegrant may work also as the carrier during the granulation process.
  • the disintegrant accelerates the disintegration not only of the tablet but also the disintegration of the granules and thus accelerates the dissolution and improves the bioavailability of enzalutamide.
  • the process of preparing a tablet composition of the present invention can comprise a step of spraying the granulation liquid (in particular as obtained in step a) of the process of preparing a tablet) on the carrier, intragranular disintegrant and optionally surfactant to obtain granules, preferably in fluid bed granulator.
  • the granules further comprise disintegrant, preferably the intragranular disintegrant is selected from sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, preferably the intragranular disintegrant is sodium croscarmellose.
  • the tablet comprises 0.5-15 wt% of the intragranular disintegrant, preferably 1-10 wt% of the intragranular disintegrant, more preferably 2-5 wt% of the intragranular disintegrant relative to the total weight of the tablet.
  • the granules further comprise a surfactant, preferably selected from sodium lauryl sulphate or poloxamer, more preferably the intragranular surfactant is sodium lauryl sulphate.
  • a surfactant preferably selected from sodium lauryl sulphate or poloxamer, more preferably the intragranular surfactant is sodium lauryl sulphate.
  • the tablet comprises 0.1-10 wt% of the intragranular surfactant, preferably 0.5-5 wt%, more preferably 0.5-3 wt% of the intragranular surfactant relative to the total weight of the tablet.
  • the tablet of the present invention comprises extragranular pharmaceutically acceptable excipients.
  • the extragranular pharmaceutically acceptable excipients are selected from one or more fillers, disintegrants, glidants, lubricants or surfactants.
  • the tablet of the present invention can comprise extragranular pharmaceutically acceptable excipients
  • the extragranular pharmaceutically acceptable excipients can comprise filler (in particular the extragranular filler can comprise microcrystalline cellulose), and disintegrant (in particular the extragranular disintegrant can comprise sodium croscarmellose), and optionally one or more further extragranular pharmaceutically acceptable excipients selected from glidant, lubricant or surfactant.
  • the extragranular filler enables the possibility of improvement the physical properties of compression mixture giving the technological process additional robustness in case when granulate with not optimal properties is obtained in the granulation process.
  • the extragranular filler By the addition of the extragranular filler the flowability and compressibility of the compression mixture can be affected and so the processability of the tabletting improved.
  • the extragranular filler is selected from lactose, mannitol, sorbitol, sucrose, maltitol, starches, dextrose, calcium phosphates, sodium or calcium carbonates, microcrystalline cellulose, preferably the extragranular filler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose.
  • the tablet comprises 5-60 wt% of the extragranular filler, preferably 5-40 wt% of the extragranular filler, more preferably 5-30 wt% of the extragranular filler, even more preferably 5-20 wt% of the extragranular filler, most preferably 5-15 wt% of the extragranular filler relative to the total weight of the tablet.
  • the extragranular disintegrant accelerates a disintegration of the tablet and thus accelerates the dissolution and improves the bioavailability of enzalutamide.
  • the extragranular disintegrant is selected from sodium croscarmellose, crosslinked polyvinylpyrrolidone, carboxymethylcellulose calcium, hydroxypropyl cellulose, low-substituted or sodium starch glycolate, preferably the extragranular disintegrant is sodium croscarmellose.
  • the tablet comprises 0.5-15 wt% of the extragranular disintegrant, preferably 4-10 wt% of the extragranular disintegrant, preferably 6-8 wt% of the extragranular disintegrant relative to the total weight of the tablet.
  • the extragranular glidant or lubricant is selected from silicon dioxide, magnesium stearate, calcium stearate, talc, stearic acid, sodium stearyl fumarate, most preferably magnesium stearate.
  • the tablet comprises 0.1-8 wt% of the extragranular glidant or lubricant, preferably 0.5-4 wt% of the extragranular glidant or lubricant, more preferably 0.5-2 wt% of the extragranular glidant or lubricant relative to the total weight of the tablet.
  • the extragranular surfactant accelerates a dissolution of active ingredient and thus improves the bioavailability of enzalutamide.
  • the extragranular surfactant is selected from sodium lauryl sulphate or poloxamer, preferably the extragranular surfactant is sodium lauryl sulphate.
  • the tablet comprises 0.1-10 wt% of the extragranular surfactant, preferably 0.5-5 wt%, more preferably 0.5-3 wt% of the extragranular surfactant relative to the total weight of the tablet.
  • the tablet comprises:
  • the extragranular filler preferably 5-30 wt% of the extragranular filler, more preferably 5-20 wt% of the extragranular filler, most preferably 5-15 wt% of the extragranular filler relative to the total weight of the tablet;
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the intragranular or the extragranular disintegrant is sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, more preferably sodium croscarmellose.
  • the glidant included in the solid dispersion is silicon dioxide.
  • the extragranular fdler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose.
  • the extragranular lubricant is magnesium stearate.
  • the surfactant, either included in the solid dispersion, the intragranular surfactant or the extragranular surfactant is sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
  • the tablet comprises:
  • the carrier preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet; 1-10 wt% of the intragranular disintegrant, more preferably 2-5 wt% of the intragranular disintegrant relative to the total weight of the tablet; optionally, 0.3-5 wt% of the glidant included in the solid dispersion, more preferably 0.5-3 wt% of the glidant included in the solid dispersion relative to the total weight of the tablet; optionally, 0.5-5 wt% of the surfactant included in the solid dispersion or the intragranular surfactant, more preferably 0.5-3 wt% of the surfactant included in the solid dispersion or the intragranular surfactant relative to the total weight of the tablet;
  • the extragranular fdler preferably 5-30 wt% of the extragranular fdler, more preferably 5-20 wt% of the extragranular fdler, most preferably 5-15 wt% of the extragranular fdler relative to the total weight of the tablet;
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the intragranular or the extragranular disintegrant is sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, more preferably sodium croscarmellose.
  • the glidant included in the solid dispersion is silicon dioxide.
  • the extragranular fdler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose.
  • the extragranular lubricant is magnesium stearate.
  • the surfactant, either included in the solid dispersion, the intragranular surfactant or the extragranular surfactant is sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
  • the tablet comprises:
  • the extragranular filler preferably 5-30 wt% of the extragranular filler, more preferably 5-20 wt% of the extragranular filler, most preferably 5-15 wt% of the extragranular filler relative to the total weight of the tablet;
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the intragranular or the extragranular disintegrant is sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, more preferably sodium croscarmellose.
  • the glidant included in the solid dispersion is silicon dioxide.
  • the extragranular filler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose.
  • the extragranular lubricant is magnesium stearate.
  • the surfactant, either included in the solid dispersion, the intragranular surfactant or the extragranular surfactant is sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
  • the concentration enhancing polymer relative to the total weight of the tablet 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet; 1-10 wt% of the intragranular disintegrant, more preferably 2-5 wt% of the intragranular disintegrant relative to the total weight of the tablet; optionally, 0.3-5 wt% of the glidant included in the solid dispersion, more preferably 0.5-3 wt% of the glidant included in the solid dispersion relative to the total weight of the tablet; optionally, 0.5-5 wt% of the surfactant included in the solid dispersion or the intragranular surfactant, more preferably 0.5-3 wt% of the surfactant included in the solid dispersion or the intragranular surfactant relative to the total weight of the tablet;
  • the extragranular filler preferably 5-30 wt% of the extragranular filler, more preferably 5-20 wt% of the extragranular filler, most preferably 5-15 wt% of the extragranular filler relative to the total weight of the tablet;
  • the intragranular or the extragranular disintegrant is sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, more preferably sodium croscarmellose.
  • the glidant included in the solid dispersion is silicon dioxide.
  • the extragranular fdler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose.
  • the extragranular lubricant is magnesium stearate.
  • the surfactant, either included in the solid dispersion, the intragranular surfactant or the extragranular surfactant is sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
  • the tablet comprises:
  • the extragranular fdler preferably 5-30 wt% of the extragranular fdler, more preferably 5-20 wt% of the extragranular fdler, most preferably 5-15 wt% of the extragranular fdler relative to the total weight of the tablet;
  • the concentration enhancing polymer is HPMC-AS and the weight ratio of enzalutamide to HPMC- AS is about 1:4.
  • the carrier is lactose or microcrystalline cellulose, more preferably lactose.
  • the intragranular or the extragranular disintegrant is sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, more preferably sodium croscarmellose.
  • the glidant included in the solid dispersion is silicon dioxide.
  • the extragranular fdler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose.
  • the extragranular lubricant is magnesium stearate.
  • the surfactant, either included in the solid dispersion, the intragranular surfactant or the extragranular surfactant is sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
  • the granulation liquid/suspension/dispersion is sprayed in the fluid bed granulator by binary spraying nozzle using compressed air onto carrier that is being fluidized in the processing bowl.
  • the solids from granulation dispersion are collected on the carrier while the granulation solvent evaporates. This way the granules of carrier, polymer, enzalutamide and optionally other excipient are formed, growing bigger through processing time/fluid bed granulation. Due to the presence of carrier in the fluid bed, the process of spraying is faster and more efficient (energy and time less consuming) in comparison to often used spray drying technique for solid dispersion preparation.
  • the granules comprising a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier are prepared by fluid bed granulation.
  • fluid bed granulation an observation regarding the formation of amorphous solid dispersions has been identified, specifically when utilizing fluid-bed granulation with HPMC-AS and CAP polymers. It is recognized by those skilled in the art that fluid-bed granulation and the spraydrying process possess distinct methodologies, especially concerning particle formation dynamics and moisture exposure. Despite these recognized differences, the tablets of the present invention demonstrate a notable absence of active ingredient diffractions in their diffractograms. This absence strongly suggests the successful formation of amorphous solid dispersions on the surface of the carrier component, thereby underscoring the effectiveness and adaptability of fluid-bed granulation in attaining the desired pharmaceutical properties of enzalutamide final dosage formulations.
  • Enzalutamide and the concentration enhancing polymer can be dissolved (or suspended) in acetone (or in a mixture of acetone and water) to obtain a granulation liquid.
  • Enzalutamide and the concentration enhancing polymer are dissolved in acetone at room temperature (room temperature can be a temperature in the range of from 15 to 30°C, in particular 20-25 °C) and mixing minimum 15 minutes to obtain a granulation liquid.
  • the granulation liquid might comprise one or more additional pharmaceutically acceptable excipients such as glidant and/or surfactant. The granulation liquid is sprayed on the carrier to obtain granules.
  • the granulation liquid is sprayed using binary nozzle and compressed air on the carrier fluidised in fluid bed granulator to obtain granules.
  • the intragranular disintegrant (and optionally surfactant) is added to the carrier before granulation step.
  • the granulate is dried and sieved, in particular through sieve with openings 0,5 -1,4 mm. Obtained dry granules are mixed with one or more extragranular pharmaceutically acceptable excipients selected from fillers, glidant, disintegrant and/or surfactant. After homogenization obtained mixture comprising granules and extragranular pharmaceutically acceptable excipients is compressed into tablets.
  • enzalutamide and the concentration enhancing polymer are dissolved in a mixture of acetone and water comprising 1-40 wt% of water, preferably 5-30 wt% of water, more preferably 10-20 wt% of water.
  • Another aspect of the present invention is a process for preparing a tablet composition comprising granules, characterized in that it comprises a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier, wherein a concentration enhancing polymer is selected from cellulose acetate phthalate, methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, preferably cellulose acetate phthalate or hydroxypropyl methyl cellulose acetate succinate, more preferably cellulose acetate phthalate.
  • a concentration enhancing polymer is selected from cellulose acetate phthalate, methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, preferably cellulose acetate phthalate or hydroxypropy
  • the process for preparing a tablet composition comprises the following steps: a) Dissolving or suspending enzalutamide, the concentration enhancing polymer and optionally glidant and/or surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; b) Spraying the granulation liquid obtained in step a) on the carrier to obtain granules, preferably in fluid bed granulator; c) Drying the granules obtained in step b): d) Sieving the dried granulate obtained in step c); e) Adding extragranular excipients to dry granules obtained in step d); f) Homogenizing the mixture obtained in step e); g) Compressing the mixture obtained in step f) into tablets; h) Optionally coating the tablets obtained in step g) with a film-coating.
  • the process for preparing a tablet composition comprises the following steps: a) Dissolving or suspending enzalutamide, the concentration enhancing polymer and optionally glidant and/or surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; b) Spraying the granulation liquid obtained in step a) on the carrier, intragranular disintegrant and optionally surfactant to obtain granules, preferably in fluid bed granulator; c) Drying the granules obtained in step b): d) Sieving the dried granulate obtained in step c); e) Adding extragranular excipients to dry granules obtained in step d); f) Homogenizing the mixture obtained in step e); g) Compressing the mixture obtained in step f) into tablets; h) Optionally coating the tablets obtained in step g) with a film-coating.
  • the present inventors also provide a tablet composition of the present invention (in particular a tablet composition comprising granules, characterized in that granules comprise a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier, wherein a concentration enhancing polymer is selected from cellulose acetate phthalate, methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, preferably cellulose acetate phthalate or hydroxypropyl methyl cellulose acetate succinate, more preferably cellulose acetate phthalate, especially a tablet composition according to any of embodiments disclosed herein), which is obtained by a process of preparing a tablet composition disclosed herein (especially which is obtained by one of the processes comprising steps a) to h) disclosed herein).
  • a concentration enhancing polymer is selected from cellulose acetate phthalate, meth
  • Step a) can be in particular
  • step b) is performed in fluid bed granulator.
  • step b) the granulation liquid obtained in step a) is sprayed on the carrier and the intragranular disintegrant to obtain granules.
  • the tablets are coated by a fdm coating, preferably PVA (Polyvinyl Alcohol) or HPMC based.
  • Film-coating has a function of distinguishing among different strengths, taste masking, to ease the swallowing of the tablet and in the case of enzalutamide, which is anticancer drug (OEB4), also protection from undesired contacts with an active ingredient.
  • the tablet compositions of the present invention can be for use in the treatment of prostate cancer, in particular castration-resistant prostate cancer.
  • Enzalutamide, CAP and optionally silicon dioxide were dispersed and dissolved or suspended in solvent to obtain granulation liquid.
  • Granulation liquid was then sprayed on the carrier (microcrystalline cellulose or lactose) and intragranular part of sodium croscarmellose in the fluid bed granulator to obtain granules.
  • Extragranular excipients were added to granulate and homogenized. Obtained tableting mixture was compressed on rotary tablet press to obtain tablets. Tablets were coated with HPMC (hydroxypropyl methylcellulose) based fdm coating.
  • Enzalutamide, methacrylic acid - ethyl acrylate copolymer (1: 1) (e.g. EUDRAGIT L 100-55) and silicon dioxide were dispersed and dissolved or suspended in solvent to obtain granulation liquid.
  • Granulation liquid was then sprayed on the carrier (microcrystalline cellulose or lactose) and intragranular part of sodium croscarmellose in the fluid bed granulator to obtain granules. Extragranular excipients were added to granulate and homogenized. Obtained tableting mixture was compressed on rotary tablet press to obtain tablets. Tablets were coated with HPMC based fdm coating.
  • Enzalutamide, HPMC-AS (MG) and optionally silicon dioxide were dispersed and dissolved or suspended in solvent to obtain granulation liquid.
  • Granulation liquid was then sprayed on the carrier (microcrystalline cellulose or lactose) and optionally intragranular part of sodium croscarmellose in the fluid bed granulator to obtain granules.
  • Extragranular excipients were added to granulate and homogenized. Obtained tableting mixture was compressed on rotary tablet press to obtain tablets. Tablets were coated with HPMC based film coating.
  • Tablets prepared according to the Example 1 were tested by “Friability of uncoated tablets”, Ph. Eur.
  • Tablets fulfil the pharmacopeia requirements of the weight loss to be maximum 1.0 % w/w.
  • tablets prepared according to Examples 1 and 3 after 6 months storing at 40 °C / 75% RV showed no conversion to crystalline enzalutamide.
  • the dissolution profile was determined under the following experimental conditions: 0.05 M Na - Phosphate Buffer pH 6.8 + 0.4 % SDS (sodium dodecyl sulfate), 900 mL, using an USP1 apparatus with 20 mesh size baskets, 100 rpm.
  • the amount of dissolved enzalutamide is determined with HPLC, by using external standard solution with known concentrations.
  • Dissolution profiles of tablets and Reference tablets Xtandi® are similar since more than 85 % of enzalutamide is dissolved in 15 minutes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a tablet composition comprising granules, characterized in that granules comprise a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier and a process for its preparation.

Description

Tablet comprising enzalutamide
Technical Field
The present invention relates to tablets comprising enzalutamide and processes for its preparation including fluid bed granulation.
Background of the invention
Enzalutamide, chemical name 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2- sulfanylideneimidazolidin-l-yl]-2-fluoro-N-methylbenzamide, was first disclosed in WO 2006/124118. It is an androgen receptor signalling inhibitor and it is indicated for the treatment of castration-resistant prostate cancer. Enzalutamide has low solubility and high permeability and is classified as BCS class II compound.
Polymorphic form A of enzalutamide and a process for preparing the crystalline form A are disclosed in WO 2014/043208 and WO 2016/194813.
Enzalutamide commercial products (brand name XTANDI®) are available in a form of a soft capsule or a film coated tablet. The film coated tablet comprises spray dried solid dispersion of enzalutamide and polymer HPMC-AS, as described in WO 2014/043208. WO 2014/043208 describes amorphous solid dispersions with numerous concentration enhancing polymers and several methods for their preparation. The most preferred are solid dispersions with HPMC-AS prepared by spray drying.
WO 2014/167428 describes enzalutamide solid dispersions with several polymers prepared by drying a solution of enzalutamide and polymer by distillation under reduced pressure.
WO 2015/118015 describes enzalutamide adsorbates comprising a surfactant and enzalutamide solid dispersions with polymers and a surfactant on a carrier. Preferred polymers are HPMC or HPMC-AS. WO 2018/199282 describes enzalutamide solid dispersions with PVA.
CN 109432016 describes ternary solid dispersions comprising enzalutamide, HPMC-AS and a third component, selected from trehalose, maltitol, cyclodextrin and Dowfax 21 A.
WO 2021/064123 describes a granulate consisting of enzalutamide solid dispersions with a cellulosic concentration enhancing polymer on a carrier. Preferred polymers are HPMC-AS and HPMCP. Granulate is prepared by fluid bed granulation by equipment commonly used.
WO 2021/240206 describes enzalutamide solid dispersions with at least one anionic polymer and/or at least one non-ionic polymer. Solid dispersions might be prepared by spray drying, fluid bed granulation or evaporation.
According to the prior art HPMC-AS is a polymer for preparing solid dispersions and the most efficient technique is spray drying. However, spray drying requires expensive equipment and the process of spray drying is extremely time consuming.
Solid dispersions can be prepared by equipment commonly used in pharmaceutical industry, e.g. fluid bed granulator. However, we have discovered that tablets comprising a granulate of enzalutamide solid dispersion with HPMC-AS prepared by fluid bed granulation method are susceptible to crushing during handling.
Consequently, there is still a need for a robust tablet, showing low friability, comprising enzalutamide solid dispersion prepared by a cost-effective process using standard equipment used in pharmaceutical technology. In addition, the tablets need to assure a good bioavailability of enzalutamide and good stability (in particular good storage stability).
Summary of the invention
The present invention comprises in particular the following items: (1) A tablet composition comprising granules, characterized in that granules comprise a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier, wherein a concentration enhancing polymer is selected from cellulose acetate phthalate, methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate or hydroxypropyl methyl cellulose acetate succinate, preferably a concentration enhancing polymer is cellulose acetate phthalate or hydroxypropyl methyl cellulose acetate succinate, more preferably a concentration enhancing polymer is cellulose acetate phthalate.
(2) The tablet composition according to item (1), wherein the concentration enhancing polymer is cellulose acetate phthalate.
(3) The tablet composition according to item (1), wherein the concentration enhancing polymer is hydroxypropyl methyl cellulose acetate succinate.
(4) The tablet composition according to any one of items (1) to (3), wherein the carrier is selected from microcrystalline cellulose, lactose, mannitol, isomalt, preferably the carrier is microcrystalline cellulose or lactose, more preferably the carrier is lactose.
(5) The tablet composition according to any one of items (1) to (4), wherein the carrier is lactose.
(6) The tablet composition according to any one of items (1) to (4), wherein the carrier is microcrystalline cellulose.
(7) The tablet composition according to any one of items (1) to (6), wherein the weight ratio of enzalutamide to the concentration enhancing polymer is from about 1: 1 to about 1:6, preferably from about 1: 1 to about 1:5, more preferably from about 1: 1.5 to about 1:4.
(8) The tablet composition according to any one of items (1) to (7), wherein the weight ratio of enzalutamide to the concentration enhancing polymer is from about 1: 1.5 to about 1:3, preferably from about 1: 1.5 to about 1:2, more preferably about 1: 1.5 or about 1:2.
(9) The tablet composition according to any one of items (1) to (7), wherein the weight ratio of enzalutamide to the concentration enhancing polymer is from about 1:2 to about 1:5, preferably from about 1:2 to about 1:4, more preferably from about 1:3 to about 1:4, even more preferably about 1:3 or about 1:4.
(10) The tablet composition according to any one of items (1) to (7), wherein the weight ratio of enzalutamide to the concentration enhancing polymer is about 1: 1.5 or about 1:2 or about 1:3 or about 1:4.
(11) The tablet composition according to any one of items (1) to (7) or item (10), wherein the weight ratio of enzalutamide to the concentration enhancing polymer is about 1: 1.5.
(12) The tablet composition according to any one of items (1) to (7) or item (10), wherein the weight ratio of enzalutamide to the concentration enhancing polymer is about 1:2.
(13) The tablet composition according to any one of items (1) to (7) or item (9), wherein the weight ratio of enzalutamide to the concentration enhancing polymer is about 1:3.
(14) The tablet composition according to any one of items (1) to (7) or item (9), wherein the weight ratio of enzalutamide to the concentration enhancing polymer is about 1:4.
(15) The tablet composition according to any one of items (1) to (14), wherein the weight ratio of enzalutamide to the carrier is from about 1 : 1 to about 1:6, preferably from about 1 :2 to about 1:5, more preferably from about 1:3 to about 1:4.5, even more preferably from about 1:3 to about 1:4, most preferably from about 1:3.5 to about 1:4.
(16) The tablet composition according to any one of items (1) to (15), wherein the weight ratio of enzalutamide to the carrier is from about 1:3 to about 1:4.5, preferably from about 1:3 to about 1:4, more preferably from about 1:3.5 to about 1:4.
(17) The tablet composition according to any one of items (1) to (16), wherein the weight ratio of enzalutamide to the carrier is from about 1:3 to about 1:4.
(18) The tablet composition according to any one of items (1) to (17), wherein the weight ratio of enzalutamide to the carrier is about 1:3.5 or about 1:4.
(19) The tablet composition according to any one of items (1) to (15), wherein the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1 : 1 : 1 to about 1:6:6, preferably from about 1: 1.5:2 to about 1:5:5, more preferably from about 1: 1.5:3 to about 1:4:4.5, even more preferably from about 1:2:3 to about 1:4:4, most preferably from about 1:3:3.5 to about 1:4:4.
(20) The tablet composition according to item (11), wherein the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1 : 1.5 :2 to about 1 : 1.5 :5, preferably from about 1: 1.5:3 to about 1: 1.5: 4.5, more preferably from about 1: 1.5:3 to about
1 : 1.5 :4, most preferably from about 1 : 1.5 :3.5 to about 1 : 1.5 :4.
(21) The tablet composition according to item (12), wherein the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1:2:2 to about 1: 1.5: 5, preferably from about 1:2:3 to about 1:2:4.5, more preferably from about 1:2:3 to about 1:2:4, most preferably from about 1:2:3.5 to about 1:2:4.
(22) The tablet composition according to item (13), wherein the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1:3:2 to about 1:3:5, preferably from about 1:3:3 to about 1:3:4.5, more preferably from about 1:3:3 to about 1:3:4, most preferably from about 1:3: 3.5 to about 1:3:4.
(23) The tablet composition according to item (14), wherein the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1:4:2 to about 1:4:5, preferably from about 1:4:3 to about 1:4:4.5, more preferably from about 1:4:3 to about 1:4:4, most preferably from about 1:4: 3.5 to about 1:4:4.
(24) The tablet composition according to any one of items (1) to (23), wherein the tablet comprises 2-50 wt% of enzalutamide, preferably 5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8-12 wt% of enzalutamide relative to the total weight of the tablet.
(25) The tablet composition according to any one of items (1) to (24), wherein the tablet comprises 10-60 wt% of the concentration enhancing polymer, preferably 15-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet.
(26) The tablet composition according to any one of items (8), (11), (12), (20) or (21), wherein the tablet comprises 2-50 wt% of enzalutamide, preferably 5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8-12 wt% of enzalutamide, and wherein the tablet comprises 10-25 wt% of the concentration enhancing polymer, preferably 15-
Figure imgf000004_0001
(l' l) The tablet composition according to any one of items (13), (14), (22) or (23), wherein the tablet comprises 2-50 wt% of enzalutamide, preferably 5-30 wt% of enzalutamide, more preferably 5- 20 wt% of enzalutamide, even more preferably 8-12 wt% of enzalutamide, and wherein the tablet comprises 25-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet.
(28) The tablet composition according to any one of items (13), (22) or (27), wherein the tablet comprises 2-50 wt% of enzalutamide, preferably 5-30 wt% of enzalutamide, more preferably 5- 20 wt% of enzalutamide, even more preferably 8-12 wt% of enzalutamide, and wherein the tablet comprises 25-35 wt% of the concentration enhancing polymer relative to the total weight of the tablet.
(29) The tablet composition according to any one of items (14), (23) or (27), wherein the tablet comprises 2-50 wt% of enzalutamide, preferably 5-30 wt% of enzalutamide, more preferably 5- 20 wt% of enzalutamide, even more preferably 8-12 wt% of enzalutamide, and wherein the tablet comprises 30-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet.
(30) The tablet composition according to any one of items (1) to (29), wherein the tablet comprises 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet.
(31) The tablet composition according to any one of items (1) to (30), wherein the solid dispersion of enzalutamide and the concentration enhancing polymer on a carrier further comprises a glidant, preferably silicon dioxide.
(32) The tablet composition according to any one of items (1) to (31), wherein the tablet comprises 0.1-10 wt% of the glidant included in the solid dispersion, more preferably 0.3-5 wt% of the glidant included in the solid dispersion, more preferably 0.5-3 wt% of the glidant included in the solid dispersion relative to the total weight of the tablet.
(33) The tablet composition according to any one of items (1) to (32), wherein the solid dispersion of enzalutamide and the concentration enhancing polymer on a carrier further comprises a surfactant, preferably selected from sodium lauryl sulphate or poloxamer, preferably sodium lauryl sulphate.
(34) The tablet composition according to any one of items (1) to (35), wherein the tablet comprises 0.1-10 wt% of the surfactant included in the solid dispersion, preferably 0.5-5 wt% of the surfactant included in the solid dispersion, more preferably 0.5-3 wt% of the surfactant included in the solid dispersion relative to the total weight of the tablet.
(35) The tablet composition according to any one of items (1) to (34), wherein the granules further comprise disintegrant, preferably selected from sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, preferably sodium croscarmellose.
(36) The tablet composition according to any one of items (1) to (35), wherein the tablet comprises 0.5-15 wt% of the intragranular disintegrant, preferably 1-10 wt% of the intragranular disintegrant, more preferably 2-5 wt% of the intragranular disintegrant relative to the total weight of the tablet.
(37) The tablet composition according to any one of items (1) to (32) or (35) to (36), wherein the granules further comprise a surfactant, preferably selected from sodium lauryl sulphate or poloxamer, preferably sodium lauryl sulphate. (38) The tablet composition according to any one of items (1) to (32) or (35) to (37), wherein the tablet comprises 0.1-10 wt% of the intragranular surfactant, preferably 0.5-5 wt% of the intragranular surfactant, more preferably 0.5-3 wt% of the intragranular surfactant relative to the total weight of the tablet.
(39) The tablet composition according to any one of items (1) to (38), wherein the tablet further comprises extragranular pharmaceutically acceptable excipients.
(40) The tablet composition according to any one of items (1) to (39), wherein the extragranular pharmaceutically acceptable excipients are selected from one or more fdlers, disintegrants, glidants, lubricants or surfactants.
(41) The tablet composition according to any one of items (1) to (40), wherein the extragranular fdler is selected from lactose, mannitol, sorbitol, sucrose, maltitol, starches, dextrose, calcium phosphates, sodium or calcium carbonates, microcrystalline cellulose, preferably microcrystalline cellulose or lactose, more preferably microcrystalline cellulose.
(42) The tablet composition according to any one of items (1) to (41), wherein the extragranular disintegrant is selected from sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, preferably sodium croscarmellose.
(43) The tablet composition according to any one of items (1) to (42), wherein the extragranular glidant or lubricant is selected from silicon dioxide, magnesium stearate, calcium stearate, talc, stearic acid, sodium stearyl fumarate, most preferably magnesium stearate.
(44) The tablet composition according to any one of items (1) to (43), wherein the extragranular surfactant is selected from sodium lauryl sulphate or poloxamer, preferably sodium lauryl sulphate.
(45) The tablet composition according to any one of items (1) to (44), wherein the tablet comprises 5-60 wt% of the extragranular filler, preferably 5-40 wt% of the extragranular filler, more preferably 5-30 wt% of the extragranular filler, even more preferably 5-20 wt% of the extragranular filler, most preferably 5-15 wt% of the extragranular filler relative to the total weight of the tablet.
(46) The tablet composition according to any one of items (1) to (45), wherein the tablet comprises 0.1-8 wt% of the extragranular glidant or lubricant, preferably 0.5-4 wt% of the extragranular glidant or lubricant, more preferably 0.5-2 wt% of the extragranular glidant or lubricant relative to the total weight of the tablet.
(47) The tablet composition according to any one of items (1) to (46), wherein the tablet comprises 0.5-15 wt% of the extragranular disintegrant, preferably 4-10 wt% of the extragranular disintegrant, preferably 6-8 wt% of the extragranular disintegrant relative to the total weight of the tablet.
(48) The tablet composition according to any one of items (1) to (47), wherein the tablet comprises 0.1-10 wt% of the extragranular surfactant, preferably 0.5-5 wt% of the extragranular surfactant, more preferably 0.5-3 wt% of the extragranular surfactant relative to the total weight of the tablet.
(49) The tablet composition according to any one of items (1) to (48), wherein the tablet comprises 40 mg or 80 mg of enzalutamide. (50) The tablet composition according to any one of items (1) to (49), wherein the granules are prepared by fluid bed granulation.
(51) A process of preparing the tablet composition according to any one of items (1) to (50) comprising the following steps: a) Dissolving or suspending enzalutamide, the concentration enhancing polymer and optionally glidant and/or surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; b) Spraying the granulation liquid obtained in step a) on the carrier to obtain granules, preferably in fluid bed granulator; c) Drying the granules obtained in step b); d) Optionally, sieving the dried granulate obtained in step c); e) Adding extragranular excipients to dry granules obtained in step d); f) Homogenizing the mixture obtained in step e); g) Compressing the mixture obtained in step f) into tablets; h) Optionally, coating the tablets obtained in step g) with a fdm-coating.
(52) A process of preparing the tablet composition according to any one of items (1) to (50) comprising the following steps: a) Dissolving or suspending enzalutamide, the concentration enhancing polymer and optionally glidant and/or surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; b) Spraying the granulation liquid obtained in step a) on the carrier, intragranular disintegrant and optionally surfactant to obtain granules, preferably in fluid bed granulator; c) Drying the granules obtained in step b); d) Optionally, sieving the dried granulate obtained in step c); e) Adding extragranular excipients to dry granules obtained in step d); f) Homogenizing the mixture obtained in step e); g) Compressing the mixture obtained in step f) into tablets; h) Optionally, coating the tablets obtained in step g) with a film-coating.
(53) The process according to item (51) or item (52), wherein step b) is performed in fluid bed granulator.
(54) The tablet composition according to any one of items (1) to (50), wherein the tablet composition is obtained by the process according to any one of items (51) to (53).
A preferred embodiment is directed to a tablet composition comprising granules, characterized in that (the) granules comprise a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier, wherein (the) concentration enhancing polymer is selected from cellulose acetate phthalate, methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, preferably cellulose acetate phthalate or hydroxypropyl methyl cellulose acetate succinate, more preferably cellulose acetate phthalate.
Brief description of the Figures
Figure 1 illustrates an X-ray powder diffraction (XRPD) pattern of Tablet 1C prepared according to Example 1 in comparison to XRPD of enzalutamide Form A.
Figure 2 illustrates an X-ray powder diffraction (XRPD) pattern of Tablet 3C prepared according to Example 3 in comparison to XRPD of enzalutamide Form A. Detailed description of the invention
One aspect of the present invention is a tablet composition comprising granules, characterized in that granules comprise a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier.
Preferably, the solid dispersion should be of an amorphous type. Thus, the tablet composition of the present invention can be a tablet composition comprising granules, characterized in that granules comprise an amorphous solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier. For the purpose of the specification, "amorphous" means a non-crystalline state that lacks the long-range order which is characteristic of a crystal. A completely amorphous material neither shows XRPD diffractions nor does it show thermal events during DSC analysis. Amorphous materials can be characterized by a complete disorder as well as a short-range order. They are distinguished from nanocrystalline materials which are characterized by an intermediate-range order and from crystalline or polycrystalline materials which are characterized by a long-range order. Amorphous solids lack long- range orientational and positional atomic or molecular order (and corresponding symmetry operators), but usually exhibit some degree of short-range orientational and/or positional order. Amorphous solids can be regarded as frozen liquids: at the molecular level the structure is liquid like, while at the macroscopic level, they have viscosities and hardness typical for solids.
As a concentration enhancing polymer may be used any polymer that is able to form a solid dispersion with enzalutamide, wherein enzalutamide is in amorphous form. In this way a bioavailability of enzalutamide is increased. Preferred polymers are appropriate for preparing solid dispersion with enzalutamide by using fluid-bed granulation technique. The concentration enhancing polymer may be selected from cellulosic or non-cellulosic polymers.
Cellulosic polymers may be neutral or ionizable in water. The cellulosic concentration enhancing polymer may be selected from hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate.
The non-cellulosic concentration enhancing polymer may selected from polyvinyl alcohol, polyvinyl pyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate), polyethyleneoxide, polyoxyethylene alkyl ethers, polymethacrylates, acrylate and methacrylate copolymers, e.g. methacrylic acid - ethyl acrylate copolymer (1: 1), graft copolymers of polyethyleneglycol, polyvinylcaprolactam and polyvinylacetate.
In one preferred embodiment of the present invention, the concentration enhancing polymer is selected from cellulose acetate phthalate (CAP), methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate (HPMCP) or hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).
In one preferred embodiment of the present invention, the concentration enhancing polymer is cellulose acetate phthalate (CAP) or hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).
In one preferred embodiment of the present invention, the concentration enhancing polymer is hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).
HPMC-AS is available in several grades. Preferable grade for preparing the solid dispersion of enzalutamide and the concentration enhancing polymer on a carrier is grade MG.
In even more preferred embodiment of the present invention, the concentration enhancing polymer is cellulose acetate phthalate (CAP). CAP is a derivative of cellulose where part of the hydroxyl groups is esterized with acetic or phthalic acid. Consequently, it is not soluble in acidic media, whereas it dissolves in neutral and alkali media. Therefore, the polymer is often used also for gastro-resistant coatings of tablets. When coating is not coherent or thick enough, or when it is dispersed along the tablet it does not necessarily react as gastro resistant, i.e. the drug can be dissolved also in lower pH media.
The carrier may be water soluble or water insoluble, for example microcrystalline cellulose, lactose, mannitol or isomalt. Lactose can be in particular lactose monohydrate.
In one embodiment of the present invention, the carrier is selected from microcrystalline cellulose, lactose, mannitol or isomalt, preferably the carrier is microcrystalline cellulose or lactose. Microcrystalline cellulose and lactose are widely used in oral pharmaceutical products. Both excipients are available in various types regarding physical properties, such as particle size, bulk density, flowability, moisture content. The type can be chosen regarding the suitability for the technological process, for example direct compression, dry or wet granulation, capsulating. Most often microcrystalline cellulose and lactose are used as a filler, while in our case they are used also as a carrier in fluid bed granulation.
Lactose is water soluble pharmaceutical excipient and thus enables faster dissolution of the tablet. Furthermore, we surprisingly found out that lactose shows better processability over microcrystalline cellulose when using fluid-bed granulation method.
In one preferred embodiment of the present invention, the carrier is lactose.
In one embodiment of the present invention, the weight ratio of enzalutamide to the concentration enhancing polymer is from about 1: 1 to about 1:6, preferably from about 1: 1 to about 1:5, more preferably from about 1: 1.5 to about 1:4.
In one embodiment of the present invention, the weight ratio of enzalutamide to the concentration enhancing polymer is from about 1:2 to about 1:5, preferably from about 1:2 to about 1:4, more preferably from about 1:3 to about 1:4, even more preferably about 1:3 or about 1:4.
In one embodiment of the present invention, the weight ratio of enzalutamide to the concentration enhancing polymer is about 1: 1.5 or about 1:2 or about 1:3 or about 1:4, most preferably 1:4.
In one preferred embodiment of the present invention, the weight ratio of enzalutamide to CAP is about 1: 1.5 or about 1:2 or about 1:3 or about 1:4, most preferably 1:4.
In one preferred embodiment of the present invention, wherein the weight ratio of enzalutamide to HPMC-AS is from about 1:2 to about 1:5, preferably from about 1:2 to about 1:4, more preferably from about 1:3 to about 1:4, even more preferably about 1:3 or about 1:4, most preferably 1:4.
In one embodiment of the present invention, the weight ratio of enzalutamide to the carrier is from about 1: 1 to about 1:6, preferably from about 1:2 to about 1:5, more preferably from about 1:3 to about 1:4.5, even more preferably from about 1:3 to about 1:4, most preferably from about 1:3.5 to about 1:4.
In one embodiment of the present invention, the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about L L l to about 1:6:6, preferably from about 1: 1.5:2 to about 1:5:5, more preferably from about 1: 1.5:3 to about 1:4:4.5, even more preferably from about 1:2:3 to about 1:4:4, most preferably from about 1:3:3.5 to about 1:4:4. Preferably, the concentration enhancing polymer is CAP. In one preferred embodiment of the present invention, the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1: 1.5:2 to about 1: 1.5:5, preferably from about 1: 1.5:3 to about 1: 1.5:4.5, more preferably from about 1: 1.5:3 to about 1: 1.5:4, most preferably from about 1: 1.5:3.5 to about 1: 1.5:4. Preferably, the concentration enhancing polymer is CAP. Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one preferred embodiment of the present invention, the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1:2:2 to about 1: 1.5:5, preferably from about 1:2:3 to about 1:2:4.5, more preferably from about 1:2:3 to about 1:2:4, most preferably from about 1:2:3.5 to about 1:2:4. Preferably, the concentration enhancing polymer is CAP. Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one preferred embodiment of the present invention, the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1:3:2 to about 1:3:5, preferably from about 1:3:3 to about 1:3:4.5, more preferably from about 1:3:3 to about 1:3:4, most preferably from about 1:3:3.5 to about 1:3:4. Preferably, the concentration enhancing polymer is CAP or HPMC-AS. Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one preferred embodiment of the present invention, the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1:4:2 to about 1:4:5, preferably from about 1:4:3 to about 1:4:4.5, more preferably from about 1:4:3 to about 1:4:4, most preferably from about 1:4:3.5 to about 1:4:4. Preferably, the concentration enhancing polymer is CAP or HPMC-AS. Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one embodiment of the present invention, the tablet comprises 2-50 wt% of enzalutamide, preferably 5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8-12 wt% of enzalutamide relative to the total weight of the tablet.
In one embodiment of the present invention, the tablet comprises 40 mg, 80 mg, 120 mg or 160 mg of enzalutamide, preferably 40 mg or 80 mg of enzalutamide. In particular, the tablet can comprise 40 mg to 160 mg of enzalutamide, preferably 40 mg to 80 mg of enzalutamide.
In one embodiment of the present invention, the tablet comprises 10-60 wt% of the concentration enhancing polymer, preferably 15-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet; and
10-25 wt% of the concentration enhancing polymer, preferably 15-20 wt% of the concentration enhancing polymer relative to the total weight of the tablet.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet; and
25-40 wt% of the concentration enhancing relative to the total weight of the tablet.
In one embodiment of the present invention, the tablet comprises 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet; 10-25 wt% of the concentration enhancing polymer, preferably 15-20 wt% of the concentration enhancing polymer relative to the total weight of the tablet; and
10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet;
25-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet; and 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet; and
10-25 wt% of the concentration enhancing polymer, preferably 15-20 wt% of the concentration enhancing polymer relative to the total weight of the tablet; wherein the concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is in the range of about 1 : 1.5 to about 1 :2, or is about 1 : 1.5 or about 1:2.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet; and
25-35 wt% of the concentration enhancing polymer relative to the total weight of the tablet; wherein the concentration enhancing polymer is CAP or HPMC-AS and the weight ratio of enzalutamide to CAP or HPMC-AS is about 1:3.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet; and
30-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet, wherein the concentration enhancing polymer is CAP or HPMC-AS and the weight ratio of enzalutamide to CAP or HPMC-AS is about 1:4.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet;
10-25 wt% of the concentration enhancing polymer, preferably 15-20 wt% of the concentration enhancing polymer relative to the total weight of the tablet; and
10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet; wherein the concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is in the range of about 1 : 1.5 to about 1 :2, or is about 1 : 1.5 or about 1:2.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet; 25-35 wt% of the concentration enhancing polymer relative to the total weight of the tablet; and 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet. wherein the concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is about 1:3.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet;
25-35 wt% of the concentration enhancing polymer relative to the total weight of the tablet; and 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet. wherein the concentration enhancing polymer is HPMC-AS and the weight ratio of enzalutamide to HPMC- AS is about 1:3.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet;
30-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet; and 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet. wherein the concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is about 1:4.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet;
30-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet; and 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet. wherein the concentration enhancing polymer is HPMC-AS and the weight ratio of enzalutamide to HPMC- AS is about 1:4.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose.
The solid dispersion of enzalutamide and the concentration enhancing polymer on a carrier may further comprise a glidant and/or surfactant.
In one embodiment of the present invention, the solid dispersion of enzalutamide and the concentration enhancing polymer on a carrier further comprises a glidant, preferably silicon dioxide. The amount of the glidant included in the solid dispersion is 0.1-10 wt% preferably 0.3-5 wt%, more preferably 0.5-3 wt% relative to the total weight of the tablet.
The surfactant may improve a wettability of enzalutamide during granulation process and improve a dissolution of the tablet. The surfactant may be selected from the group of anionic, cationic or non-ionic surfactants e.g. lecithin, sodium lauryl sulphate, phospholipids, poloxamers. In one embodiment of the present invention, the solid dispersion of enzalutamide and the concentration enhancing polymer on a carrier further comprises a surfactant, preferably selected from sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate. The amount of the surfactant included in the solid dispersion is 0.1-10 wt% preferably 0.5-5 wt%, more preferably 0.5-3 wt% relative to the total weight of the tablet.
In addition, a disintegrant may be added to a granulation mixture. The disintegrant may work also as the carrier during the granulation process. Furthermore, the disintegrant accelerates the disintegration not only of the tablet but also the disintegration of the granules and thus accelerates the dissolution and improves the bioavailability of enzalutamide. In particular, the process of preparing a tablet composition of the present invention can comprise a step of spraying the granulation liquid (in particular as obtained in step a) of the process of preparing a tablet) on the carrier, intragranular disintegrant and optionally surfactant to obtain granules, preferably in fluid bed granulator.
In one embodiment of the present invention, the granules further comprise disintegrant, preferably the intragranular disintegrant is selected from sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, preferably the intragranular disintegrant is sodium croscarmellose.
In one embodiment of the present invention, the tablet comprises 0.5-15 wt% of the intragranular disintegrant, preferably 1-10 wt% of the intragranular disintegrant, more preferably 2-5 wt% of the intragranular disintegrant relative to the total weight of the tablet.
In one embodiment of the present invention, the granules further comprise a surfactant, preferably selected from sodium lauryl sulphate or poloxamer, more preferably the intragranular surfactant is sodium lauryl sulphate.
In one embodiment of the present invention, the tablet comprises 0.1-10 wt% of the intragranular surfactant, preferably 0.5-5 wt%, more preferably 0.5-3 wt% of the intragranular surfactant relative to the total weight of the tablet.
The tablet of the present invention comprises extragranular pharmaceutically acceptable excipients.
In one embodiment of the present invention, the extragranular pharmaceutically acceptable excipients are selected from one or more fillers, disintegrants, glidants, lubricants or surfactants.
In particular, the tablet of the present invention can comprise extragranular pharmaceutically acceptable excipients, the extragranular pharmaceutically acceptable excipients can comprise filler (in particular the extragranular filler can comprise microcrystalline cellulose), and disintegrant (in particular the extragranular disintegrant can comprise sodium croscarmellose), and optionally one or more further extragranular pharmaceutically acceptable excipients selected from glidant, lubricant or surfactant.
The extragranular filler enables the possibility of improvement the physical properties of compression mixture giving the technological process additional robustness in case when granulate with not optimal properties is obtained in the granulation process. By the addition of the extragranular filler the flowability and compressibility of the compression mixture can be affected and so the processability of the tabletting improved.
In one embodiment of the present invention, the extragranular filler is selected from lactose, mannitol, sorbitol, sucrose, maltitol, starches, dextrose, calcium phosphates, sodium or calcium carbonates, microcrystalline cellulose, preferably the extragranular filler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose.
In one embodiment of the present invention, the tablet comprises 5-60 wt% of the extragranular filler, preferably 5-40 wt% of the extragranular filler, more preferably 5-30 wt% of the extragranular filler, even more preferably 5-20 wt% of the extragranular filler, most preferably 5-15 wt% of the extragranular filler relative to the total weight of the tablet.
The extragranular disintegrant accelerates a disintegration of the tablet and thus accelerates the dissolution and improves the bioavailability of enzalutamide.
In one embodiment of the present invention, the extragranular disintegrant is selected from sodium croscarmellose, crosslinked polyvinylpyrrolidone, carboxymethylcellulose calcium, hydroxypropyl cellulose, low-substituted or sodium starch glycolate, preferably the extragranular disintegrant is sodium croscarmellose.
In one embodiment of the present invention, the tablet comprises 0.5-15 wt% of the extragranular disintegrant, preferably 4-10 wt% of the extragranular disintegrant, preferably 6-8 wt% of the extragranular disintegrant relative to the total weight of the tablet.
In one embodiment of the present invention, the extragranular glidant or lubricant is selected from silicon dioxide, magnesium stearate, calcium stearate, talc, stearic acid, sodium stearyl fumarate, most preferably magnesium stearate.
In one embodiment of the present invention, the tablet comprises 0.1-8 wt% of the extragranular glidant or lubricant, preferably 0.5-4 wt% of the extragranular glidant or lubricant, more preferably 0.5-2 wt% of the extragranular glidant or lubricant relative to the total weight of the tablet.
The extragranular surfactant accelerates a dissolution of active ingredient and thus improves the bioavailability of enzalutamide.
In one embodiment of the present invention, the extragranular surfactant is selected from sodium lauryl sulphate or poloxamer, preferably the extragranular surfactant is sodium lauryl sulphate.
In one embodiment of the present invention, the tablet comprises 0.1-10 wt% of the extragranular surfactant, preferably 0.5-5 wt%, more preferably 0.5-3 wt% of the extragranular surfactant relative to the total weight of the tablet.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet;
10-25 wt% of the concentration enhancing polymer, preferably 15-20 wt% of the concentration enhancing polymer relative to the total weight of the tablet; and
10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet; 1-10 wt% of the intragranular disintegrant, more preferably 2-5 wt% of the intragranular disintegrant relative to the total weight of the tablet; optionally, 0.3-5 wt% of the glidant included in the solid dispersion, more preferably 0.5-3 wt% of the glidant included in the solid dispersion relative to the total weight of the tablet; optionally, 0.5-5 wt% of the surfactant included in the solid dispersion or the intragranular surfactant, more preferably 0.5-3 wt% of the surfactant included in the solid dispersion or the intragranular surfactant relative to the total weight of the tablet;
5-40 wt% of the extragranular filler, preferably 5-30 wt% of the extragranular filler, more preferably 5-20 wt% of the extragranular filler, most preferably 5-15 wt% of the extragranular filler relative to the total weight of the tablet;
4-10 wt% of the extragranular disintegrant, preferably 6-8 wt% of the extragranular disintegrant relative to the total weight of the tablet;
0.5-4 wt% of the extragranular glidant or lubricant, more preferably 0.5-2 wt% of the extragranular glidant or lubricant relative to the total weight of the tablet; optionally, 0.5-5 wt% of the extragranular surfactant, more preferably 0.5-3 wt% of the extragranular surfactant relative to the total weight of the tablet; wherein the concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is in the range of about 1 : 1.5 to about 1 :2, or is about 1 : 1.5 or about 1:2.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose. Preferably, the intragranular or the extragranular disintegrant is sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, more preferably sodium croscarmellose. Preferably, the glidant included in the solid dispersion is silicon dioxide. Preferably, the extragranular fdler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose. Preferably, the extragranular lubricant is magnesium stearate. Preferably, the surfactant, either included in the solid dispersion, the intragranular surfactant or the extragranular surfactant, is sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet;
25-35 wt% of the concentration enhancing polymer relative to the total weight of the tablet; 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet; 1-10 wt% of the intragranular disintegrant, more preferably 2-5 wt% of the intragranular disintegrant relative to the total weight of the tablet; optionally, 0.3-5 wt% of the glidant included in the solid dispersion, more preferably 0.5-3 wt% of the glidant included in the solid dispersion relative to the total weight of the tablet; optionally, 0.5-5 wt% of the surfactant included in the solid dispersion or the intragranular surfactant, more preferably 0.5-3 wt% of the surfactant included in the solid dispersion or the intragranular surfactant relative to the total weight of the tablet;
5-40 wt% of the extragranular fdler, preferably 5-30 wt% of the extragranular fdler, more preferably 5-20 wt% of the extragranular fdler, most preferably 5-15 wt% of the extragranular fdler relative to the total weight of the tablet;
4-10 wt% of the extragranular disintegrant, preferably 6-8 wt% of the extragranular disintegrant relative to the total weight of the tablet;
0.5-4 wt% of the extragranular glidant or lubricant, more preferably 0.5-2 wt% of the extragranular glidant or lubricant relative to the total weight of the tablet; optionally, 0.5-5 wt% of the extragranular surfactant, more preferably 0.5-3 wt% of the extragranular surfactant relative to the total weight of the tablet; wherein the concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is about 1:3.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose. Preferably, the intragranular or the extragranular disintegrant is sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, more preferably sodium croscarmellose. Preferably, the glidant included in the solid dispersion is silicon dioxide. Preferably, the extragranular fdler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose. Preferably, the extragranular lubricant is magnesium stearate. Preferably, the surfactant, either included in the solid dispersion, the intragranular surfactant or the extragranular surfactant, is sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet;
25-35 wt% of the concentration enhancing polymer relative to the total weight of the tablet; 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet; 1-10 wt% of the intragranular disintegrant, more preferably 2-5 wt% of the intragranular disintegrant relative to the total weight of the tablet; optionally, 0.3-5 wt% of the glidant included in the solid dispersion, more preferably 0.5-3 wt% of the glidant included in the solid dispersion relative to the total weight of the tablet; optionally, 0.5-5 wt% of the surfactant included in the solid dispersion or the intragranular surfactant, more preferably 0.5-3 wt% of the surfactant included in the solid dispersion or the intragranular surfactant relative to the total weight of the tablet;
5-40 wt% of the extragranular filler, preferably 5-30 wt% of the extragranular filler, more preferably 5-20 wt% of the extragranular filler, most preferably 5-15 wt% of the extragranular filler relative to the total weight of the tablet;
4-10 wt% of the extragranular disintegrant, preferably 6-8 wt% of the extragranular disintegrant relative to the total weight of the tablet;
0.5-4 wt% of the extragranular glidant or lubricant, more preferably 0.5-2 wt% of the extragranular glidant or lubricant relative to the total weight of the tablet; optionally, 0.5-5 wt% of the extragranular surfactant, more preferably 0.5-3 wt% of the extragranular surfactant relative to the total weight of the tablet; wherein the concentration enhancing polymer is HPMC-AS and the weight ratio of enzalutamide to HPMC- AS is about 1:3.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose. Preferably, the intragranular or the extragranular disintegrant is sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, more preferably sodium croscarmellose. Preferably, the glidant included in the solid dispersion is silicon dioxide. Preferably, the extragranular filler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose. Preferably, the extragranular lubricant is magnesium stearate. Preferably, the surfactant, either included in the solid dispersion, the intragranular surfactant or the extragranular surfactant, is sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet;
30-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet; 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet; 1-10 wt% of the intragranular disintegrant, more preferably 2-5 wt% of the intragranular disintegrant relative to the total weight of the tablet; optionally, 0.3-5 wt% of the glidant included in the solid dispersion, more preferably 0.5-3 wt% of the glidant included in the solid dispersion relative to the total weight of the tablet; optionally, 0.5-5 wt% of the surfactant included in the solid dispersion or the intragranular surfactant, more preferably 0.5-3 wt% of the surfactant included in the solid dispersion or the intragranular surfactant relative to the total weight of the tablet;
5-40 wt% of the extragranular filler, preferably 5-30 wt% of the extragranular filler, more preferably 5-20 wt% of the extragranular filler, most preferably 5-15 wt% of the extragranular filler relative to the total weight of the tablet;
4-10 wt% of the extragranular disintegrant, preferably 6-8 wt% of the extragranular disintegrant relative to the total weight of the tablet;
0.5-4 wt% of the extragranular glidant or lubricant, more preferably 0.5-2 wt% of the extragranular glidant or lubricant relative to the total weight of the tablet; optionally, 0.5-5 wt% of the extragranular surfactant, more preferably 0.5-3 wt% of the extragranular surfactant relative to the total weight of the tablet; wherein the concentration enhancing polymer is CAP and the weight ratio of enzalutamide to CAP is about 1:4. Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose. Preferably, the intragranular or the extragranular disintegrant is sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, more preferably sodium croscarmellose. Preferably, the glidant included in the solid dispersion is silicon dioxide. Preferably, the extragranular fdler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose. Preferably, the extragranular lubricant is magnesium stearate. Preferably, the surfactant, either included in the solid dispersion, the intragranular surfactant or the extragranular surfactant, is sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
In one preferred embodiment of the present invention, the tablet comprises:
5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8- 12 wt% of enzalutamide relative to the total weight of the tablet;
30-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet; 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet; 1-10 wt% of the intragranular disintegrant, more preferably 2-5 wt% of the intragranular disintegrant relative to the total weight of the tablet; optionally, 0.3-5 wt% of the glidant included in the solid dispersion, more preferably 0.5-3 wt% of the glidant included in the solid dispersion relative to the total weight of the tablet; optionally, 0.5-5 wt% of the surfactant included in the solid dispersion or the intragranular surfactant, more preferably 0.5-3 wt% of the surfactant included in the solid dispersion or the intragranular surfactant relative to the total weight of the tablet;
5-40 wt% of the extragranular fdler, preferably 5-30 wt% of the extragranular fdler, more preferably 5-20 wt% of the extragranular fdler, most preferably 5-15 wt% of the extragranular fdler relative to the total weight of the tablet;
4-10 wt% of the extragranular disintegrant, preferably 6-8 wt% of the extragranular disintegrant relative to the total weight of the tablet;
0.5-4 wt% of the extragranular glidant or lubricant, more preferably 0.5-2 wt% of the extragranular glidant or lubricant relative to the total weight of the tablet; optionally, 0.5-5 wt%, more preferably 0.5-3 wt% of the extragranular surfactant relative to the total weight of the tablet; wherein the concentration enhancing polymer is HPMC-AS and the weight ratio of enzalutamide to HPMC- AS is about 1:4.
Preferably, the carrier is lactose or microcrystalline cellulose, more preferably lactose. Preferably, the intragranular or the extragranular disintegrant is sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, more preferably sodium croscarmellose. Preferably, the glidant included in the solid dispersion is silicon dioxide. Preferably, the extragranular fdler is microcrystalline cellulose or lactose, more preferably microcrystalline cellulose. Preferably, the extragranular lubricant is magnesium stearate. Preferably, the surfactant, either included in the solid dispersion, the intragranular surfactant or the extragranular surfactant, is sodium lauryl sulphate or poloxamer, more preferably sodium lauryl sulphate.
The granulation liquid/suspension/dispersion is sprayed in the fluid bed granulator by binary spraying nozzle using compressed air onto carrier that is being fluidized in the processing bowl. The solids from granulation dispersion are collected on the carrier while the granulation solvent evaporates. This way the granules of carrier, polymer, enzalutamide and optionally other excipient are formed, growing bigger through processing time/fluid bed granulation. Due to the presence of carrier in the fluid bed, the process of spraying is faster and more efficient (energy and time less consuming) in comparison to often used spray drying technique for solid dispersion preparation.
In one embodiment of the present invention, the granules comprising a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier are prepared by fluid bed granulation. In the systematic analysis of the data, an observation regarding the formation of amorphous solid dispersions has been identified, specifically when utilizing fluid-bed granulation with HPMC-AS and CAP polymers. It is recognized by those skilled in the art that fluid-bed granulation and the spraydrying process possess distinct methodologies, especially concerning particle formation dynamics and moisture exposure. Despite these recognized differences, the tablets of the present invention demonstrate a notable absence of active ingredient diffractions in their diffractograms. This absence strongly suggests the successful formation of amorphous solid dispersions on the surface of the carrier component, thereby underscoring the effectiveness and adaptability of fluid-bed granulation in attaining the desired pharmaceutical properties of enzalutamide final dosage formulations.
Enzalutamide and the concentration enhancing polymer can be dissolved (or suspended) in acetone (or in a mixture of acetone and water) to obtain a granulation liquid. In particular, Enzalutamide and the concentration enhancing polymer are dissolved in acetone at room temperature (room temperature can be a temperature in the range of from 15 to 30°C, in particular 20-25 °C) and mixing minimum 15 minutes to obtain a granulation liquid. In addition, the granulation liquid might comprise one or more additional pharmaceutically acceptable excipients such as glidant and/or surfactant. The granulation liquid is sprayed on the carrier to obtain granules. In particular, the granulation liquid is sprayed using binary nozzle and compressed air on the carrier fluidised in fluid bed granulator to obtain granules. The intragranular disintegrant (and optionally surfactant) is added to the carrier before granulation step. After spraying, the granulate is dried and sieved, in particular through sieve with openings 0,5 -1,4 mm. Obtained dry granules are mixed with one or more extragranular pharmaceutically acceptable excipients selected from fillers, glidant, disintegrant and/or surfactant. After homogenization obtained mixture comprising granules and extragranular pharmaceutically acceptable excipients is compressed into tablets.
Alternatively, enzalutamide and the concentration enhancing polymer are dissolved in a mixture of acetone and water comprising 1-40 wt% of water, preferably 5-30 wt% of water, more preferably 10-20 wt% of water.
Another aspect of the present invention is a process for preparing a tablet composition comprising granules, characterized in that it comprises a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier, wherein a concentration enhancing polymer is selected from cellulose acetate phthalate, methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, preferably cellulose acetate phthalate or hydroxypropyl methyl cellulose acetate succinate, more preferably cellulose acetate phthalate.
In one embodiment of the present invention, the process for preparing a tablet composition comprises the following steps: a) Dissolving or suspending enzalutamide, the concentration enhancing polymer and optionally glidant and/or surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; b) Spraying the granulation liquid obtained in step a) on the carrier to obtain granules, preferably in fluid bed granulator; c) Drying the granules obtained in step b): d) Sieving the dried granulate obtained in step c); e) Adding extragranular excipients to dry granules obtained in step d); f) Homogenizing the mixture obtained in step e); g) Compressing the mixture obtained in step f) into tablets; h) Optionally coating the tablets obtained in step g) with a film-coating.
In one embodiment of the present invention, the process for preparing a tablet composition comprises the following steps: a) Dissolving or suspending enzalutamide, the concentration enhancing polymer and optionally glidant and/or surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; b) Spraying the granulation liquid obtained in step a) on the carrier, intragranular disintegrant and optionally surfactant to obtain granules, preferably in fluid bed granulator; c) Drying the granules obtained in step b): d) Sieving the dried granulate obtained in step c); e) Adding extragranular excipients to dry granules obtained in step d); f) Homogenizing the mixture obtained in step e); g) Compressing the mixture obtained in step f) into tablets; h) Optionally coating the tablets obtained in step g) with a film-coating.
The above processes are applicable for preparing the tablet composition according to any of embodiments disclosed above.
The present inventors also provide a tablet composition of the present invention (in particular a tablet composition comprising granules, characterized in that granules comprise a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier, wherein a concentration enhancing polymer is selected from cellulose acetate phthalate, methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, preferably cellulose acetate phthalate or hydroxypropyl methyl cellulose acetate succinate, more preferably cellulose acetate phthalate, especially a tablet composition according to any of embodiments disclosed herein), which is obtained by a process of preparing a tablet composition disclosed herein (especially which is obtained by one of the processes comprising steps a) to h) disclosed herein).
Step a) can be in particular
- dissolving or suspending enzalutamide, and the concentration enhancing polymer in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; or
- dissolving or suspending enzalutamide, and the concentration enhancing polymer, and one of glidant and surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; or
- dissolving or suspending enzalutamide, and the concentration enhancing polymer, and glidant and surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid.
In one embodiment of the present invention, step b) is performed in fluid bed granulator.
In one embodiment of the present invention, in step b) the granulation liquid obtained in step a) is sprayed on the carrier and the intragranular disintegrant to obtain granules.
Optionally, the tablets are coated by a fdm coating, preferably PVA (Polyvinyl Alcohol) or HPMC based. Film-coating has a function of distinguishing among different strengths, taste masking, to ease the swallowing of the tablet and in the case of enzalutamide, which is anticancer drug (OEB4), also protection from undesired contacts with an active ingredient.
The tablet compositions of the present invention can be for use in the treatment of prostate cancer, in particular castration-resistant prostate cancer.
The following non-limiting examples are presented to illustrate the present invention.
Examples
Example 1
Figure imgf000020_0001
Enzalutamide, CAP and optionally silicon dioxide were dispersed and dissolved or suspended in solvent to obtain granulation liquid. Granulation liquid was then sprayed on the carrier (microcrystalline cellulose or lactose) and intragranular part of sodium croscarmellose in the fluid bed granulator to obtain granules. Extragranular excipients were added to granulate and homogenized. Obtained tableting mixture was compressed on rotary tablet press to obtain tablets. Tablets were coated with HPMC (hydroxypropyl methylcellulose) based fdm coating.
Example 2
Figure imgf000020_0002
Figure imgf000021_0001
Enzalutamide, methacrylic acid - ethyl acrylate copolymer (1: 1) (e.g. EUDRAGIT L 100-55) and silicon dioxide were dispersed and dissolved or suspended in solvent to obtain granulation liquid. Granulation liquid was then sprayed on the carrier (microcrystalline cellulose or lactose) and intragranular part of sodium croscarmellose in the fluid bed granulator to obtain granules. Extragranular excipients were added to granulate and homogenized. Obtained tableting mixture was compressed on rotary tablet press to obtain tablets. Tablets were coated with HPMC based fdm coating.
Example 3
Figure imgf000021_0002
Enzalutamide, HPMC-AS (MG) and optionally silicon dioxide were dispersed and dissolved or suspended in solvent to obtain granulation liquid. Granulation liquid was then sprayed on the carrier (microcrystalline cellulose or lactose) and optionally intragranular part of sodium croscarmellose in the fluid bed granulator to obtain granules. Extragranular excipients were added to granulate and homogenized. Obtained tableting mixture was compressed on rotary tablet press to obtain tablets. Tablets were coated with HPMC based film coating.
Example 4
Tablets prepared according to the Example 1 were tested by “Friability of uncoated tablets”, Ph. Eur.
2.9.7.
Tablets fulfil the pharmacopeia requirements of the weight loss to be maximum 1.0 % w/w.
Example 5
Analytical methods XRPD: Powder diffractograms were collected using X-ray powder diffractometer (PANalytical X’Pert PRO MPD, Almelo, NL) with Cu Ka radiation (X = 1.5418 A) at 45 kV and 40 mA and X'Celerator detector. Measurement was performed in the 2Theta range from 3 to 32.5°, with step size 0.033° and integration time 2000s.
XRPD of Tablet 1C prepared according to Example 1 is presented in Figure 1.
XRPD of Tablet 3C prepared according to Example 3 is presented in Figure 2.
Furthermore, tablets prepared according to Examples 1 and 3 after 6 months storing at 40 °C / 75% RV showed no conversion to crystalline enzalutamide.
Example 6
Analytical methods
The dissolution profile was determined under the following experimental conditions: 0.05 M Na - Phosphate Buffer pH 6.8 + 0.4 % SDS (sodium dodecyl sulfate), 900 mL, using an USP1 apparatus with 20 mesh size baskets, 100 rpm. The amount of dissolved enzalutamide is determined with HPLC, by using external standard solution with known concentrations.
Figure imgf000022_0001
Dissolution profiles of tablets and Reference tablets Xtandi® are similar since more than 85 % of enzalutamide is dissolved in 15 minutes.

Claims

Claims
1. A tablet composition comprising granules, characterized in that granules comprise a solid dispersion of enzalutamide and a concentration enhancing polymer on a carrier, wherein a concentration enhancing polymer is selected from cellulose acetate phthalate, methacrylic acid - ethyl acrylate copolymer (1: 1), hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, preferably cellulose acetate phthalate or hydroxypropyl methyl cellulose acetate succinate, more preferably cellulose acetate phthalate.
2. The tablet composition according to claim 1, wherein the carrier is selected from microcrystalline cellulose, lactose, mannitol, isomalt, preferably the carrier is microcrystalline cellulose or lactose, more preferably the carrier is lactose.
3. The tablet composition according to claim 1 or claim 2, wherein the weight ratio of enzalutamide to the concentration enhancing polymer is from about 1 : 1 to about 1:6, preferably from about 1 : 1 to about 1:5, more preferably from about 1: 1.5 to about 1:4.
4. The tablet composition according to any one of claims 1 to 3, wherein the weight ratio of enzalutamide to the concentration enhancing polymer to the carrier is from about 1 : 1 : 1 to about 1:6:6, preferably from about 1: 1.5:2 to about 1:5:5, more preferably from about 1: 1.5:3 to about 1:4:4.5, even more preferably from about 1:2:3 to about 1:4:4, most preferably from about 1:3:3.5 to about 1:4:4.
5. The tablet composition according to any one of claims 1 to 4, wherein the tablet comprises 2-50 wt% of enzalutamide, preferably 5-30 wt% of enzalutamide, more preferably 5-20 wt% of enzalutamide, even more preferably 8-12 wt% of enzalutamide relative to the total weight of the tablet.
6. The tablet composition according to any one of claims 1 to 5, wherein the tablet comprises 10-60 wt% of the concentration enhancing polymer, preferably 15-40 wt% of the concentration enhancing polymer relative to the total weight of the tablet.
7. The tablet composition according to any one of claims 1 to 6, wherein the tablet comprises 10-60 wt% of the carrier, preferably 20-50 wt% of the carrier, more preferably 25-45 wt% of the carrier, most preferably 30-40 wt% of the carrier relative to the total weight of the tablet.
8. The tablet composition according to any one of claims 1 to 7, wherein the granules further comprise disintegrant, preferably selected from sodium croscarmellose, crosslinked polyvinylpyrrolidone or sodium starch glycolate, preferably sodium croscarmellose.
9. The tablet composition according to any one of claims 1 to 8, wherein the tablet further comprises extragranular pharmaceutically acceptable excipients selected from one or more fdlers, disintegrants, glidants, lubricants, surfactants.
10. A process of preparing the tablet composition according to any one of claims 1 to 9, comprising the following steps: a) Dissolving or suspending enzalutamide, the concentration enhancing polymer and optionally glidant and/or surfactant, in acetone or in a mixture of acetone and water, preferably in acetone, to obtain a granulation liquid; b) Spraying the granulation liquid obtained in step a) on the carrier, optionally intragranular disintegrant and optionally surfactant to obtain granules, preferably in fluid bed granulator; c) Drying the granules obtained in step b); d) Optionally, sieving the dried granulate obtained in step c); e) Adding extragranular excipients to dry granules obtained in step d); f) Homogenizing the mixture obtained in step e); g) Compressing the mixture obtained in step f) into tablets; h) Optionally, coating the tablets obtained in step g) with a film-coating.
PCT/EP2024/086209 2023-12-13 2024-12-13 Tablet comprising enzalutamide Pending WO2025125565A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SIP-202300159 2023-12-13
SI202300159 2023-12-13

Publications (1)

Publication Number Publication Date
WO2025125565A1 true WO2025125565A1 (en) 2025-06-19

Family

ID=94173162

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/086209 Pending WO2025125565A1 (en) 2023-12-13 2024-12-13 Tablet comprising enzalutamide

Country Status (1)

Country Link
WO (1) WO2025125565A1 (en)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006124118A1 (en) 2005-05-13 2006-11-23 The Regents Of The University Of California Diarylhydantoin compounds
WO2014043208A1 (en) 2012-09-11 2014-03-20 Medivation Prostate Therapeutics, Inc. Formulations of enzalutamide
WO2014167428A2 (en) 2013-04-10 2014-10-16 Shilpa Medicare Limited Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-n-methylbenzamide
WO2015118015A1 (en) 2014-02-05 2015-08-13 Lek Pharmaceuticals D.D. Solid pharmaceutical compositions of androgen receptor antagonists
WO2016194813A1 (en) 2015-05-29 2016-12-08 アステラス製薬株式会社 Process for producing enzalutamide crystal form
WO2018199282A1 (en) 2017-04-28 2018-11-01 アステラス製薬株式会社 Orally administrable enzalutamide-containing pharmaceutical composition
CN109432016A (en) 2018-12-26 2019-03-08 广州中医药大学(广州中医药研究院) A kind of tertiary solid preparation and preparation method thereof of the miscellaneous Shandong amine of grace
WO2021064123A1 (en) 2019-10-03 2021-04-08 Synthon B.V. Pharmaceutical composition comprising enzalutamide
WO2021240206A1 (en) 2020-05-24 2021-12-02 Lotus International Pte. Ltd. Enzalutamide formulation

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006124118A1 (en) 2005-05-13 2006-11-23 The Regents Of The University Of California Diarylhydantoin compounds
WO2014043208A1 (en) 2012-09-11 2014-03-20 Medivation Prostate Therapeutics, Inc. Formulations of enzalutamide
WO2014167428A2 (en) 2013-04-10 2014-10-16 Shilpa Medicare Limited Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-n-methylbenzamide
WO2015118015A1 (en) 2014-02-05 2015-08-13 Lek Pharmaceuticals D.D. Solid pharmaceutical compositions of androgen receptor antagonists
WO2016194813A1 (en) 2015-05-29 2016-12-08 アステラス製薬株式会社 Process for producing enzalutamide crystal form
WO2018199282A1 (en) 2017-04-28 2018-11-01 アステラス製薬株式会社 Orally administrable enzalutamide-containing pharmaceutical composition
CN109432016A (en) 2018-12-26 2019-03-08 广州中医药大学(广州中医药研究院) A kind of tertiary solid preparation and preparation method thereof of the miscellaneous Shandong amine of grace
WO2021064123A1 (en) 2019-10-03 2021-04-08 Synthon B.V. Pharmaceutical composition comprising enzalutamide
US20220347102A1 (en) * 2019-10-03 2022-11-03 Synthon B.V. Pharmaceutical composition comprising enzalutamide
WO2021240206A1 (en) 2020-05-24 2021-12-02 Lotus International Pte. Ltd. Enzalutamide formulation

Similar Documents

Publication Publication Date Title
KR100634953B1 (en) Formulations in biologically enhanced oral solid dosage forms comprising eprosartan
US6515010B1 (en) Carvedilol methanesulfonate
CA2424001C (en) Oral preparations with favorable disintegration characteristics
WO2002069888A2 (en) Serotonin reuptake inhibitor formulations
WO2016062860A1 (en) Amorphous vortioxetine hydrobromide
WO2009121871A1 (en) Pharmaceutical composition comprising candesartan
WO2008083130A2 (en) Amorphous and crystalline form a of carvedilol phosphate
CN101087589B (en) Solid pharmaceutical composition comprising valsartan
EP2323634A1 (en) Ropinirole composition
WO2022180582A1 (en) Oral pharmaceutical composition of arsenic trioxide
EP1033974B1 (en) High drug load immediate and modified release oral dosage formulations and processes for their manufacture
WO2024096838A1 (en) A pharmaceutical composition comprising solid dispersion of empagliflozin
WO2011135581A2 (en) Pharmaceutical compositions of dronedarone
US7959948B2 (en) Pharmaceutical composition of quetiapine fumarate
WO2025125565A1 (en) Tablet comprising enzalutamide
CA3089537A1 (en) Pharmaceutical compositions comprising ibrutinib
CA2591983A1 (en) Pharmaceutical compositions comprising amorphous benzimidazole compounds
US20120178810A1 (en) Extended release formulation of an antiepileptic agent
EP4279075A1 (en) A pharmaceutical composition comprising elagolix
WO2025212071A1 (en) A solid dispersion of enzalutamide
WO2022243886A1 (en) Pharmaceutical composition of ivosidenib
WO2024115680A1 (en) Ribociclib salts and formulations thereof
HUP0600839A2 (en) Solid pharmaceutical composition containing polymorph i of clopidogrel hydrogensulfate and process for the preparation thereof
JP2018024628A (en) Amorphous solid dispersion containing tolvaptan and method for producing the same
WO2025109605A1 (en) Stable pharmaceutical compositions of enzalutamide

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24833251

Country of ref document: EP

Kind code of ref document: A1