WO2023174937A1 - Particles comprising non-crystalline odevixibat - Google Patents

Particles comprising non-crystalline odevixibat Download PDF

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Publication number
WO2023174937A1
WO2023174937A1 PCT/EP2023/056485 EP2023056485W WO2023174937A1 WO 2023174937 A1 WO2023174937 A1 WO 2023174937A1 EP 2023056485 W EP2023056485 W EP 2023056485W WO 2023174937 A1 WO2023174937 A1 WO 2023174937A1
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WO
WIPO (PCT)
Prior art keywords
odevixibat
particles
water
mixture
coating layer
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PCT/EP2023/056485
Other languages
French (fr)
Inventor
Hannes Lengauer
Veronika WERNER
Herbert Silberberger
Günther Guggenberger
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Sandoz Ag
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Publication of WO2023174937A1 publication Critical patent/WO2023174937A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the invention relates to particles comprising odevixibat in a non-crystalline form and to a process for the preparation thereof.
  • the invention further relates to a pharmaceutical composition of odevixibat comprising a plurality of said particles.
  • the particles and the pharmaceutical composition can be used as a medicament, e.g. in the treatment of liver diseases.
  • the invention further relates to odevixibat-2-pentanol solvate, which is useful for the preparation of particles comprising odevixibat in a non-crystalline form, a process for the preparation thereof, and to the use of odevixibat-2-pentanol solvate for the preparation of particles comprising odevixibat in a non-crystalline form.
  • Odevixibat (also referred to as A4250) is identified by CAS Registry Number 501692- 44-0 and is chemically designated as l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(7V- ⁇ (R)-a-[7V-((S)-l -carboxypropyl) carbamoyl]-4-hydroxybenzyl ⁇ carbamoylmethoxy)- 2,3,4,5-tetrahydro-l,2,5-benzothiadiazepine.
  • the compound which is disclosed in Example 29 of WO 03/022286 has the following structural formula:
  • WO 2019/245448 discloses polymorphs of odevixibat, in particular crystal modifications 1 and 2. Modification 1 is suggested for use in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and disorders, liver diseases and disorders, including progressive familial intrahepatic cholestasis (PFIC). WO 2019/245448 further discloses a pharmaceutical composition comprising modification 1.
  • Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter (IB AT).
  • IB AT ileal bile acid transporter
  • odevixibat inhibits reabsorption of bile acids from the ileum into the hepatic portal circulation. Bile acids that are not reabsorbed from the ileum are instead excreted in the feces. The overall removal of bile acids from the enterohepatic circulation results in a decrease in the level of bile acids in serum and in the liver.
  • odevixibat or a pharmaceutically acceptable salt thereof is useful in the treatment of liver diseases that are associated with elevated levels of bile acid such as cholestatic liver diseases, e.g. biliary atresia, PFIC, Alagille syndrome (ALGS), primary biliary cholangitis and paediatric cholestatic pruritus.
  • cholestatic liver diseases e.g. biliary atresia, PFIC, Alagille syndrome (ALGS), primary biliary cholangitis and paediatric cholestatic pruritus.
  • WO 2012/064266 suggests odevixibat in the prophylaxis or treatment of a liver disease.
  • Odevixibat was approved for medical use in the United States and in the European Union in July 2021. Sold under the tradename Bylvay, odevixibat is available as an oral formulation in the form of hard capsules comprising 200 pg, 400 pg, 600 pg or 1200 pg of odevixibat.
  • WO 2019/245449 discloses a multiparticulate pharmaceutical formulation of odevixibat comprising small particles of microcrystalline cellulose (MCC) coated with odevixibat and a film-forming polymer such as HPMC.
  • the pharmaceutical formulation comprises odevixibat in crystalline form, in particular crystal modification 1 of odevixibat.
  • a process for the coating of MCC spheres using a solution of HPMC with suspended odevixibat involves several elaborate steps, including sieving of the active pharmaceutical ingredient (API), wetting and homogenizing using an Ultra Turrax, followed by mixing with the HPMC solution and wet milling using a kolloid mill until optical acceptance criteria (size of agglomerates) are fulfilled.
  • the coating process is performed in a fluid bed coater with Wurster insert, using water as single solvent.
  • Another object of the invention was to provide odevixibat-coated particles wherein, unlike WO 2019/245448, a crystal modification of odevixibat in the final product is avoided.
  • the present invention relates to particles comprising a core and a coating layer wherein the coating layer comprises odevixibat in a non-crystalline form.
  • the invention further relates to a pharmaceutical composition of odevixibat comprising said particles.
  • the particles or the pharmaceutical composition of the present invention are for use as a medicament.
  • the particles or the pharmaceutical composition of the present invention are for use in the treatment or prevention of a liver disease.
  • the present invention relates to a process for the preparation of said particles, the process comprising the step of preparing a coating solution of odevixibat in a mixture of a water-miscible organic solvent and water.
  • the invention also relates to odevixibat-2-pentanol solvate, which is particularly suitable for the preparation of particles comprising odevixibat in a non-crystalline form, and to a process for the preparation thereof comprising the steps of (i) providing a suspension of odevixibat in 2-pentanol; (ii) heating the suspension to form a clear solution; and (iii) crystallizing odevixibat-2-pentanol solvate from the solution obtained in step (ii).
  • the present invention relates to the use of odevixibat-2-pentanol solvate for the manufacture of particles containing odevixibat in non-crystalline form.
  • Figure 1 Powder X-ray diffractogram of amorphous odevixibat
  • FIG. 2 NMR spectrum (1H-NMR) of odevixibat crystal modification 1 (upper panel), odevixibat-2-pentanol solvate (middle panel) and amorphous odevixibat (bottom panel)
  • odevixibat by switching from water to a solvent mixture of water and a water-miscible organic solvent a solution of odevixibat is obtained which is suitable as a coating solution for coating odevixibat onto inert cores such as microcrystalline cellulose (MCC) spheres or sugar spheres.
  • MCC microcrystalline cellulose
  • the process of the invention has several advantages.
  • the odevixibat- coated particles obtained by the inventive process exhibit a good content uniformity and an advantageous release profile of the active ingredient odevixibat.
  • the coating solution of the present invention is easier to handle than a coating suspension such as disclosed in WO 2019/245449 and less elaborate steps are required for the preparation and analysis of the coating solution comprising odevixibat.
  • the solvent mixture used allows to lower the temperature of the coating process, for example from 80°C to 60°C using a water-miscible organic solvent/water mixture, which results in less thermic stress of the final product.
  • any form of odevixibat (crystalline or amorphous) can be used as a starting compound.
  • odevixibat crystalline or amorphous
  • a solution of odevixibat in a solvent mixture of water and a water-miscible organic solvent allows to obtain odevixibat in a non-crystalline form within the coating layer.
  • a solvent mixture of water and a water- miscible organic solvent such as ethanol allows to avoid blistering and peeling off. Therefore, the present invention allows to achieve a continuous film of odevixibat on inert cores with no blistering or peeling off of the coating layer.
  • a solvent mixture of water and a water-miscible organic solvent such as ethanol was unexpectedly found to retain excellent processibility.
  • particles comprising amorphous odevixibat or odevixibat in a solid dispersion remain chemically stable upon storage, for example throughout their shelf-life.
  • the coating process of the invention has superior properties in terms of suitability for scale-up and with respect to cost effectiveness.
  • the present invention relates to particles comprising a core and a coating layer, wherein the coating layer comprises odevixibat in a non-crystalline form.
  • the core of each particle may be a pellet, a granule, a minitablet, a bead, a microparticle or a microsphere.
  • the term “core” refers to an inert core and may also be referred to as a “neutral core”.
  • Inert or neutral cores are based on, for example, microcrystalline cellulose (MCC), or sugar (e.g. sucrose) alone or in combination with starch (e.g. com starch), or sucrose alone or in combination with lactose.
  • MCC microcrystalline cellulose
  • sugar e.g. sucrose
  • starch e.g. com starch
  • sucrose alone or in combination with lactose.
  • the inert or neutral cores are preferably spherical in shape.
  • the cores are preferably MCC spheres or sugar spheres, more preferably sugar spheres.
  • the sugars spheres comprise sucrose alone or in combination with starch.
  • the cores do
  • the term “particle” as used herein refers to a particle comprising a core and a coating layer.
  • the coating layer comprises odevixibat, preferably odevixibat in a non-crystalline form.
  • the coating layer does not comprise odevixibat in a crystalline form.
  • odevixibat in a non-crystalline form or “non-crystalline form of odevixibat” refer to neat amorphous odevixibat or to amorphous odevixibat in a solid dispersion.
  • amorphous refers to a solid form of a compound that is not crystalline. An amorphous compound possesses no long-range order but only displays short-range order and does not display a definitive X-ray diffraction pattern with reflections, thus resulting in broad scattering. According to literature, long-range order e.g.
  • Figure 1 shows the powder X-ray diffractogram of amorphous odevixibat.
  • the bottom panel of Figure 2 shows the NMR spectrum (1H-NMR) of amorphous odevixibat.
  • solid dispersion refers to a system in a solid state (as opposed to a liquid or gaseous state) wherein one component is dispersed more or less evenly throughout the other component or components, e.g. in the context of the present invention amorphous odevixibat within a film-forming polymer.
  • Odevixibat is present in the particles of the invention in free form or as a pharmaceutically acceptable salt of odevixibat.
  • odevixibat is present in free form.
  • the coating layer comprises odevixibat in neat amorphous form or in a solid dispersion.
  • the coating layer can further comprise a film-forming polymer, such as a cellulose-based polymer, a polysaccharide-based polymer, an A-vinylpyrrolidone-based polymer, an acrylate, an acrylamide, or copolymers thereof.
  • a film-forming polymer such as a cellulose-based polymer, a polysaccharide-based polymer, an A-vinylpyrrolidone-based polymer, an acrylate, an acrylamide, or copolymers thereof.
  • suitable film-forming polymers include polyvinyl alcohol (PVA) , polyvinyl acetate phthalate (PVAP), polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), methacrylic acid copolymers, starch, hydroxypropyl starch, chitosan, shellac, methyl cellulose, hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC; or hypromellose), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), as well as combinations thereof.
  • PVA polyvinyl alcohol
  • PVAP polyvinyl acetate phthalate
  • PVAP polyethylene glycol
  • PVP polyvinylpyrrolidone
  • methacrylic acid copolymers starch
  • the coating layer comprises hydroxypropyl methylcellulose as the filmforming polymer.
  • HPMC exhibit a viscosity (mPa.s 2% in water at 20°C) of from 2.4 to 6.0, e.g. from 2.4 to 3.6 or from 4.0 to 6.0.
  • suitable examples of HPMC are characterized by a methoxyl substitution of from 28.0 to 30.0, a hydroxypropoxyl substitution of from 7.0 to 12.0, and a loss on drying (weight %) of 5.0% at maximum.
  • HPMC corresponding to the above characteristics is commercially available by Dupont under the tradename Methocel® premium E3 and Methocel® premium E5.
  • the coating layer comprises a solid dispersion comprising odevixibat and a film-forming polymer, preferably odevixibat and HPMC.
  • the particles have an average D50 particle size of between about 100 pm and about 1500 pm.
  • the particles Preferably, have an average D50 particle size of between about 500 pm and about 1200 pm in size, more preferably of between about 600 pm and about 800 pm, even more preferably of about 700 pm.
  • the particle size is determined microscopically.
  • Suitable microscopes include a digital microscope, i.e. an optical microscope equipped with a digital camera, such as Keyence VHX-5000 microscope, e.g. equipped with a 200-2000x objective.
  • an “average D50 particle size” refers to the Particle Size Distribution D50, which is also known as the median diameter, and is the value of the particle diameter at 50% in the cumulative distribution. In other words, the portions of particles with diameters smaller and larger than the average D50 particle size are 50%.
  • each particle contains odevixibat in an amount of from about 0.1% w/w to about 5.0% w/w based on the total weight of the particle.
  • each particle contains odevixibat in an amount of from about 0.5% w/w to about 2.0% w/w based on the total weight of the particle.
  • each particle contains odevixibat in an amount of about 0.5% w/w based on the total weight of the particle.
  • each particle contains odevixibat in an amount of about 1.5% w/w based on the total weight of the particle.
  • the coating layer of the particles has a thickness of between about 1.5 and about 2.5 pm or between about 6.5 and about 7.5 pm. In a preferred embodiment the coating layer of the particles has a thickness of between about 2 and about 3 pm. In another preferred embodiment the coating layer of the particles has a thickness of about 7 pm.
  • the particles of the present invention can be obtained by spraying the coating layer as a solution of odevixibat, and optionally a film-forming polymer, in a mixture of a water- miscible organic solvent and water onto the particles.
  • the mixture of a water-miscible organic solvent and water is a mixture of a water-miscible alcohol and water, preferably a mixture of a water-miscible alcohol selected from the group consisting of methanol, ethanol, 1 -propanol and 2-propanol, and water.
  • the water-miscible alcohol is ethanol.
  • the mixture of a water-miscible organic solvent and water comprises from about 10% w/w to about 20% w/w, preferably about 13% w/w of a water-miscible organic solvent based on the total weight of the mixture.
  • the solution of odevixibat or a pharmaceutically acceptable salt thereof, and optionally the film-forming polymer is prepared by (i) dissolving the film-forming polymer (e.g. HPMC) in a mixture of a water-miscible organic solvent and water, (ii) dissolving odevixibat in a mixture of a water-miscible organic solvent and water, and (iii) combining the solutions obtained in step (i) and step (ii).
  • the film-forming polymer e.g. HPMC
  • the mixture of a water-miscible organic solvent and water is a mixture of a water-miscible alcohol and water, preferably a mixture of a water-miscible alcohol selected from the group consisting of methanol, ethanol, 1 -propanol and 2- propanol, and water.
  • the water-miscible alcohol is ethanol.
  • the particles of the invention can be regarded as a pharmaceutical composition, in particular as a multiparticulate pharmaceutical composition. Further, the particles can also be processed into oral dosage forms, particularly an oral dosage form, e.g. filled into capsules or sachets or the particles can be compressed into tablets. These dosage forms also represent pharmaceutical compositions including the particles of the invention.
  • the invention further relates to a pharmaceutical composition and/or to an oral dosage form of odevixibat comprising the particles disclosed herein.
  • the invention further relates to a pharmaceutical composition and/or to an oral dosage form of odevixibat comprising a plurality of said particles.
  • the pharmaceutical composition can be in the form of a tablet or may constitute a formulation, wherein the particles are contained within a sachet or a capsule.
  • An exemplary capsule is a hard capsule, e.g. containing HPMC and MCC as excipients. The capsules can either be swallowed as a whole or are sprinkled onto food.
  • a multiparticulate formulation containing low doses of odevixibat is advantageous since such a formulation enables weight-based dosing and may be particularly suitable for administering to paediatric patients.
  • the pharmaceutical formulation is a paediatric formulation.
  • the odevixibat-coated particle or the tablet comprising the odevixibat-coated particles may further be coated, e.g. with an enteric coating.
  • the dosage form of the present invention may contain odevixibat in an amount of from about 0.05% w/w to about 5.0% w/w based on the total weight of the dosage form.
  • the dosage form of the present invention can contain 0.1 to 5 mg odevixibat, preferably 0.2 to 2 mg, in particular 200 pg, 400 pg, 600 pg or 1200 pg of odevixibat.
  • the odevixibat-coated particles or the dosage form comprising the odevixibat-coated particles can be used as a medicament. Therefore, the invention further relates to the odevixibat-coated particles described herein or the pharmaceutical compositions or dosage forms comprising the odevixibat-coated particles described herein for use as a medicament.
  • the odevixibat-coated particles or the pharmaceutical composition or dosage forms comprising the odevixibat-coated particles can be used in the treatment or prevention of a liver disease such as a bile acid-dependent disease, progressive familial intrahepatic cholestasis (PFIC), or biliary atresia.
  • a liver disease such as a bile acid-dependent disease, progressive familial intrahepatic cholestasis (PFIC), or biliary atresia.
  • the invention relates to a process for the preparation of the odevixibat- coated particles disclosed herein.
  • the process for the preparation of the odevixibat-coated particles comprises the step of preparing a coating solution of odevixibat in a mixture of a water-miscible organic solvent and water. Therefore, any form of odevixibat including odevixibat in free form or a pharmaceutically acceptable salt thereof, amorphous odevixibat, any crystalline modification of odevixibat or any solvate thereof is simply dissolved in a mixture of a water-miscible organic solvent and water. In a particularly preferred embodiment, odevixibat-2-pentanol solvate is dissolved in a mixture of a water-miscible organic solvent and water.
  • the mixture of a water-miscible organic solvent and water is a mixture of a water-miscible alcohol and water, preferably a mixture of a water-miscible alcohol selected from the group consisting of methanol, ethanol, 1 -propanol and 2- propanol, and water.
  • the water-miscible alcohol is ethanol.
  • the mixture of a water-miscible organic solvent and water comprises from about 10% w/w to about 20% w/w, preferably 10% w/w to about 15% w/w, e.g. about 13% w/w of a water-miscible organic solvent based on the total weight of the mixture.
  • the process for the preparation of odevixibat-coated particles comprises the step of preparing a coating solution of odevixibat and a film-forming polymer in a mixture of a water-miscible organic solvent and water.
  • the coating solution is prepared by
  • step (iii) combining the solutions obtained in step (i) and step (ii).
  • the film-forming polymer can be any one of those described above.
  • the film-forming polymer is HPMC.
  • the process for the preparation of the odevixibat-coated particles further comprises the step of spraying the coating solution onto the cores.
  • particles comprising a core and a coating layer are obtained, wherein the coating layer comprises odevixibat in a noncrystalline form.
  • the cores can be any of those described above.
  • the cores are MCC spheres or sugar spheres.
  • a typical process for the coating of MCC or sugar spheres with a film former and a solution of odevixibat is described in the following.
  • a film-forming polymer e.g. HPMC
  • HPMC water-miscible organic solvent
  • H2O a water-miscible organic solvent
  • the mixture can be a mixture of ethanol (e.g. 13% w/w) and H2O.
  • odevixibat preferably in the form of odevixibat-2-pentanol solvate
  • a water-miscible organic solvent e.g. ethanol
  • H2O a mixture of ethanol (e.g. 13% w/w) and H2O
  • the amount of coating solution used in the process is determined accordingly in order to reach a desired drug load of the particles, for example a final drug load of 0.5% or 1.5% based on the total weight of the particle.
  • MCC spheres or sugar spheres are coated using the previously prepared coating solution:
  • the coated spheres are then collected and fractionated by sieving.
  • the fractions >500 pm and ⁇ 1200 pm are analyzed by XRD (crystallinity), HPLC (drug content) and by microscope (coating thickness).
  • the invention further relates to odevixibat-coated particles obtainable by the process described herein.
  • odevixibat-coated particles described herein odevixibat-2- pentanol-solvate is particularly suitable.
  • the present invention relates in a further aspect to odevixibat-2-pentanol- solvate, particularly to a crystalline form of odevixibat-2-pentanol-solvate, and to a process for its preparation.
  • Example 29 of WO 2003/022286 yields odevixibat free compound as a “white solid” after preparative HPLC. This material is not crystalline.
  • WO 2019/245448 describes two polymorphs of odevixibat, modification 1 and modification 2.
  • Modification 1 is a channel hydrate containing up to 2 mol eq. of water. At 30% relative humidity (RH) modification 1 is present as a sesquihydrate containing about 1.5 mol eq. of water.
  • NMR data (1H-NMR) of modification 1 is shown in Figure 2 (upper panel).
  • Modification 2 is a mixed hydrate/solvate and exists as isomorphic solvates. Modification 2 may comprise MeOH, EtOH, 2-PrOH, ACT, ACNL, 1,4-DX, DMF or DMSO. Upon drying, the organic solvent is released and modification 2 transforms to modification 1.
  • modification 1 and modification 2 are thus associated with certain disadvantages.
  • modification 2 is not stable, and modification l is a variable hydrate containing varying proportions of water, which is likely to result in problems with regard to content uniformity.
  • the present invention relates to a crystalline form of odevixibat 2- pentanol solvate.
  • the novel crystalline solvate can be obtained by crystallization of odevixibat (e.g. obtained according to WO 2003/022286, example 29) from 2-pentanol.
  • Odevixibat 2-pentanol solvate according to the invention preferably contains approximately 1 mol eq. 2-pentanol, as determined by nuclear magnetic resonance (NMR). NMR data (1H-NMR) of odevixibat 2-pentanol solvate is shown in Figure 2 (middle panel).
  • the present invention relates to a crystalline form of odevixibat 2-pentanol solvate characterized by having an X-ray powder diffraction (XRPD) pattern [powder X- ray diffractogram - PXRD] comprising reflections at 2-Theta angles of (4.6 ⁇ 0.2)°, (5.6 ⁇ 0.2)°, (6.6 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphal,2 radiation having a wavelength of 0.15419 nm ( Figure 3).
  • XRPD X-ray powder diffraction
  • the present invention relates to a crystalline form of odevixibat 2- pentanol solvate characterized by having an X-ray powder diffraction (XRPD) pattern [powder X-ray diffractogram - PXRD] comprising reflections at 2-Theta angles of (4.6 ⁇ 0.2)°, (5.6 ⁇ 0.2)°, (6.6 ⁇ 0.2)°, (7.0 ⁇ 0.2)°, (8.7 ⁇ 0.2)°, (10.5 ⁇ 0.2)°, (18.1 ⁇ 0.2)°, (21.5 ⁇ 0.2)°, (21.9 ⁇ 0.2)°, (22.7 ⁇ 0.2)°, (23.4 ⁇ 0.2)°, (24.2 ⁇ 0.2)°, (24.9 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphal,2 radiation having a wavelength of 0.15419 nm ( Figure 3).
  • XRPD X-ray powder diffraction
  • the present invention relates to a crystalline form of odevixibat 2- pentanol solvate characterized by having an X-ray powder diffraction (XRPD) pattern [powder X-ray diffractogram - PXRD] comprising reflections at 2-Theta angles of (4.6 ⁇ 0.2)°, (5.6 ⁇ 0.2)°, (6.6 ⁇ 0.2)°, (7.0 ⁇ 0.2)°, (8.4 ⁇ 0.2)°, (8.7 ⁇ 0.2)°, (9.1 ⁇ 0.2)°, (9.3 ⁇ 0.2)°, (10.5 ⁇ 0.2)°, (11.2 ⁇ 0.2)°, (11.5 ⁇ 0.2)°, (11.7 ⁇ 0.2)°, (12.1 ⁇ 0.2)°, (13.0 ⁇ 0.2)°, (13.3 ⁇ 0.2)°, (13.8 ⁇ 0.2)°, (14.2 ⁇ 0.2)°, (14.5 ⁇ 0.2)°, (15.5 ⁇ 0.2)°
  • the invention further relates to a process for the preparation of odevixibat-2-pentanol solvate comprising:
  • step (iii) crystallizing odevixibat-2-pentanol solvate as defined herein from the solution obtained in step (ii).
  • the invention further relates to odevixibat 2-pentanol solvate obtainable by the process described herein.
  • Another subject of the present invention is the use of odevixibat-2-pentanol solvate for preparing odevixibat in non-crystalline form, in particular the use for preparing odevixibiat in form of a solid dispersion.
  • odevixibat-2-pentanol solvate is suitable for the preparation of odevixibat-coated particles using the process described herein.
  • odevixibat-2-pentanol solvate is suitable for the preparation of odevixibat-coated particles using the process for coating of MCC and sugar spheres with a solution of odevixibat and HPMC as film-forming polymer.
  • the invention relates to the use of odevixibat-2-pentanol solvate as described herein or to the use of odevixibat-2-pentanol solvate obtained by the process described herein for the manufacture of particles containing odevixibat in non-crystalline form.
  • Said particles comprising odevixibat in non-crystalline form are particularly suitable for the treatment of a liver disease.
  • the present invention further relates to the use of the particles described herein for the manufacture of a medicament for the treatment of a liver disease, e.g. such as bile aciddependent liver diseases, and particularly cholestatic liver diseases such as biliary atresia, progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome (ALGS) and paediatric cholestatic pruritus.
  • a liver disease e.g. such as bile aciddependent liver diseases, and particularly cholestatic liver diseases such as biliary atresia, progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome (ALGS) and paediatric cholestatic pruritus.
  • the present invention further relates to a method of treating or preventing a liver disease, comprising administering a therapeutically effective amount of the particles described herein or the pharmaceutical composition described herein to a patient in need of such treatment.
  • Powder X-ray diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphal,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector.
  • Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40 s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions.
  • a typical precision of the 2- Theta values is in the range of ⁇ 0.2° 2-Theta, preferably of ⁇ 0.1° 2-Theta.
  • Reflection positions of crystalline odevixibat 2-pentanol in the range of from 2 to 30° 2- Theta; a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably of ⁇ 0.1° 2- Theta.
  • the crystalline form of odevixibat-2-pentanol solvate was investigated by DSC, which was performed on a Mettler Polymer DSC R instrument.
  • the sample (4.25 mg) was heated in a 40 microliter aluminium pan with a pierced aluminium lid from 25 to 120°C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.
  • the DSC curve (see Figure 5) of the crystalline odevixibat-2-pentanol of the present invention shows an endotherm with an onset temperature of about 93°C, which is due to a melting process.
  • MCC spheres (Vivapur® MCC sphere 700) were coated in a fluidized bed coater with Wurster insert using the previously prepared coating solution, aiming a final 0.5% drug load.
  • the coated spheres were then collected and fractionated by sieving. The fraction >500 pm and ⁇ 1200 pm was weighted, resulting in 58.5 g (78% yield) and over 90% API recovery (determined by HPLC). XRD confirmed no crystalline reflexes. A coating thickness of 7 pm was determined using a Keyence VHX-5000 microscope equipped with a Keyence VHX-5020 camera.
  • the coated spheres were then collected and fractionated by sieving. The fraction >500 pm and ⁇ 1200 pm were weighted, resulting in 70.0 g (98% yield) and over 90% API recovery (determined by HPLC). XRD confirmed no crystalline reflexes.
  • Microcrystalline cellulose spheres were coated with a coating suspension of odevixibat comprising 1500 g/batch microcrystalline cellulose spheres 700 (Vivapur® MCC sphere 700), 7.5 g/batch odevixibat, 30 g/batch hypromellose 3 mPa.s (Methocel® E3 premium) and 337.5 g/batch purified water to obtain particles containing 0.5% w/w odevixibat. Crystalline odevixibat was used.

Abstract

The invention relates to particles comprising odevixibat in a non-crystalline form and to a process for the preparation thereof. The invention further relates to a pharmaceutical composition and/or oral dosage form of odevixibat comprising a plurality of said particles. The particles and the pharmaceutical composition can be used as a medicament, e.g. in the treatment of liver diseases. The invention further relates to odevixibat-2-pentanol solvate which is useful for the preparation of particles comprising odevixibat in a non-crystalline form, a process for the preparation thereof, and to the use of odevixibat-2-pentanol solvate for the preparation of particles comprising odevixibat in a non-crystalline form.

Description

Particles comprising non-crystalline odevixibat
FIELD OF THE INVENTION
The invention relates to particles comprising odevixibat in a non-crystalline form and to a process for the preparation thereof. The invention further relates to a pharmaceutical composition of odevixibat comprising a plurality of said particles. The particles and the pharmaceutical composition can be used as a medicament, e.g. in the treatment of liver diseases. The invention further relates to odevixibat-2-pentanol solvate, which is useful for the preparation of particles comprising odevixibat in a non-crystalline form, a process for the preparation thereof, and to the use of odevixibat-2-pentanol solvate for the preparation of particles comprising odevixibat in a non-crystalline form.
BACKGROUND OF THE INVENTION
Odevixibat (also referred to as A4250) is identified by CAS Registry Number 501692- 44-0 and is chemically designated as l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(7V- {(R)-a-[7V-((S)-l -carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)- 2,3,4,5-tetrahydro-l,2,5-benzothiadiazepine. The compound which is disclosed in Example 29 of WO 03/022286 has the following structural formula:
Figure imgf000003_0001
WO 2019/245448 discloses polymorphs of odevixibat, in particular crystal modifications 1 and 2. Modification 1 is suggested for use in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and disorders, liver diseases and disorders, including progressive familial intrahepatic cholestasis (PFIC). WO 2019/245448 further discloses a pharmaceutical composition comprising modification 1. Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter (IB AT). In particular, odevixibat inhibits reabsorption of bile acids from the ileum into the hepatic portal circulation. Bile acids that are not reabsorbed from the ileum are instead excreted in the feces. The overall removal of bile acids from the enterohepatic circulation results in a decrease in the level of bile acids in serum and in the liver.
Therefore, odevixibat or a pharmaceutically acceptable salt thereof is useful in the treatment of liver diseases that are associated with elevated levels of bile acid such as cholestatic liver diseases, e.g. biliary atresia, PFIC, Alagille syndrome (ALGS), primary biliary cholangitis and paediatric cholestatic pruritus.
Accordingly, WO 2012/064266 suggests odevixibat in the prophylaxis or treatment of a liver disease.
Odevixibat was approved for medical use in the United States and in the European Union in July 2021. Sold under the tradename Bylvay, odevixibat is available as an oral formulation in the form of hard capsules comprising 200 pg, 400 pg, 600 pg or 1200 pg of odevixibat.
WO 2019/245449 discloses a multiparticulate pharmaceutical formulation of odevixibat comprising small particles of microcrystalline cellulose (MCC) coated with odevixibat and a film-forming polymer such as HPMC. The pharmaceutical formulation comprises odevixibat in crystalline form, in particular crystal modification 1 of odevixibat. Further disclosed is a process for the coating of MCC spheres using a solution of HPMC with suspended odevixibat. The preparation of the coating suspension involves several elaborate steps, including sieving of the active pharmaceutical ingredient (API), wetting and homogenizing using an Ultra Turrax, followed by mixing with the HPMC solution and wet milling using a kolloid mill until optical acceptance criteria (size of agglomerates) are fulfilled. The coating process is performed in a fluid bed coater with Wurster insert, using water as single solvent.
The process disclosed in WO 2019/245449 is laborious and time consuming, both in terms of preparation and analysis. Besides, scale-up of this process is not straightforward due to the complex preparation and analysis steps required. Furthermore, the process does not necessarily result in a sufficient content uniformity of odevixibat on the coated spheres. In view of the above, it was an object of the invention to provide an improved process for the preparation of odevixibat-coated particles. In particular, it was an object to provide a process involving less elaborate steps for the preparation and analysis. A further object was to provide a process providing reliably good content uniformity of odevixibat on coated particles.
Another object of the invention was to provide odevixibat-coated particles wherein, unlike WO 2019/245448, a crystal modification of odevixibat in the final product is avoided.
SUMMARY OF THE INVENTION
The present invention relates to particles comprising a core and a coating layer wherein the coating layer comprises odevixibat in a non-crystalline form.
The invention further relates to a pharmaceutical composition of odevixibat comprising said particles.
The particles or the pharmaceutical composition of the present invention are for use as a medicament. In particular, the particles or the pharmaceutical composition of the present invention are for use in the treatment or prevention of a liver disease.
In addition, the present invention relates to a process for the preparation of said particles, the process comprising the step of preparing a coating solution of odevixibat in a mixture of a water-miscible organic solvent and water.
The invention also relates to odevixibat-2-pentanol solvate, which is particularly suitable for the preparation of particles comprising odevixibat in a non-crystalline form, and to a process for the preparation thereof comprising the steps of (i) providing a suspension of odevixibat in 2-pentanol; (ii) heating the suspension to form a clear solution; and (iii) crystallizing odevixibat-2-pentanol solvate from the solution obtained in step (ii).
Furthermore, the present invention relates to the use of odevixibat-2-pentanol solvate for the manufacture of particles containing odevixibat in non-crystalline form. BRIEF DESCRIPTION OF THE FIGURES
Figure 1 : Powder X-ray diffractogram of amorphous odevixibat
Figure 2: NMR spectrum (1H-NMR) of odevixibat crystal modification 1 (upper panel), odevixibat-2-pentanol solvate (middle panel) and amorphous odevixibat (bottom panel)
Figure 3 : Powder X-ray diffractogram of odevixibat-2-pentanol solvate
Figure 4: Fourier transform infrared spectrum of odevixibat-2-pentanol solvate
Figure 5: Differential scanning calorimetry (DSC) curve of odevixibat-2-pentanol solvate
DETAILED DESCRIPTION OF THE INVENTION
According to the invention it was surprisingly found that by switching from water to a solvent mixture of water and a water-miscible organic solvent a solution of odevixibat is obtained which is suitable as a coating solution for coating odevixibat onto inert cores such as microcrystalline cellulose (MCC) spheres or sugar spheres.
Unexpectedly, the process of the invention has several advantages. Thus, the odevixibat- coated particles obtained by the inventive process exhibit a good content uniformity and an advantageous release profile of the active ingredient odevixibat.
Moreover, the coating solution of the present invention is easier to handle than a coating suspension such as disclosed in WO 2019/245449 and less elaborate steps are required for the preparation and analysis of the coating solution comprising odevixibat.
Further advantageously, the solvent mixture used allows to lower the temperature of the coating process, for example from 80°C to 60°C using a water-miscible organic solvent/water mixture, which results in less thermic stress of the final product.
As a further advantage, in the process of the invention any form of odevixibat (crystalline or amorphous) can be used as a starting compound. As a consequence, there is no need for the preparation of a particular crystalline form of odevixibat before preparation of the coating solution.
Very surprisingly, it was found according to the invention that a solution of odevixibat in a solvent mixture of water and a water-miscible organic solvent allows to obtain odevixibat in a non-crystalline form within the coating layer. In particular, it was surprisingly found that using a solvent mixture of water and a water- miscible organic solvent such as ethanol allows to avoid blistering and peeling off. Therefore, the present invention allows to achieve a continuous film of odevixibat on inert cores with no blistering or peeling off of the coating layer. On the other hand, a solvent mixture of water and a water-miscible organic solvent such as ethanol was unexpectedly found to retain excellent processibility.
As a further advantage it was found that particles comprising amorphous odevixibat or odevixibat in a solid dispersion remain chemically stable upon storage, for example throughout their shelf-life.
Finally, the coating process of the invention has superior properties in terms of suitability for scale-up and with respect to cost effectiveness.
Accordingly, in a first aspect, the present invention relates to particles comprising a core and a coating layer, wherein the coating layer comprises odevixibat in a non-crystalline form.
The core of each particle may be a pellet, a granule, a minitablet, a bead, a microparticle or a microsphere. As used herein, the term “core” refers to an inert core and may also be referred to as a “neutral core”. Inert or neutral cores are based on, for example, microcrystalline cellulose (MCC), or sugar (e.g. sucrose) alone or in combination with starch (e.g. com starch), or sucrose alone or in combination with lactose. The inert or neutral cores are preferably spherical in shape. According to the invention, the cores are preferably MCC spheres or sugar spheres, more preferably sugar spheres. In a preferred embodiment the sugars spheres comprise sucrose alone or in combination with starch. Further preferably, the cores do not contain odevixibat.
The term “particle” as used herein refers to a particle comprising a core and a coating layer. According to the invention, the coating layer comprises odevixibat, preferably odevixibat in a non-crystalline form.
Preferably, the coating layer does not comprise odevixibat in a crystalline form.
The terms “odevixibat in a non-crystalline form” or “non-crystalline form of odevixibat” refer to neat amorphous odevixibat or to amorphous odevixibat in a solid dispersion. As used herein, “amorphous” refers to a solid form of a compound that is not crystalline. An amorphous compound possesses no long-range order but only displays short-range order and does not display a definitive X-ray diffraction pattern with reflections, thus resulting in broad scattering. According to literature, long-range order e.g. extends over approximately 100 to 1000 atoms and more, whereas short-range order is over a few atoms only (see “Fundamentals of Powder Diffraction and Structural Characterization of Materials” by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3). Figure 1 shows the powder X-ray diffractogram of amorphous odevixibat. The bottom panel of Figure 2 shows the NMR spectrum (1H-NMR) of amorphous odevixibat.
The term “solid dispersion” as used herein refers to a system in a solid state (as opposed to a liquid or gaseous state) wherein one component is dispersed more or less evenly throughout the other component or components, e.g. in the context of the present invention amorphous odevixibat within a film-forming polymer.
Odevixibat is present in the particles of the invention in free form or as a pharmaceutically acceptable salt of odevixibat. Preferably, odevixibat is present in free form.
In one embodiment of the particles comprising a core and a coating layer, the coating layer comprises odevixibat in neat amorphous form or in a solid dispersion.
The coating layer can further comprise a film-forming polymer, such as a cellulose-based polymer, a polysaccharide-based polymer, an A-vinylpyrrolidone-based polymer, an acrylate, an acrylamide, or copolymers thereof. Examples of suitable film-forming polymers include polyvinyl alcohol (PVA) , polyvinyl acetate phthalate (PVAP), polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), methacrylic acid copolymers, starch, hydroxypropyl starch, chitosan, shellac, methyl cellulose, hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC; or hypromellose), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), as well as combinations thereof. In a preferred embodiment, the coating layer comprises hydroxypropyl methylcellulose as the filmforming polymer. Suitable examples of HPMC exhibit a viscosity (mPa.s 2% in water at 20°C) of from 2.4 to 6.0, e.g. from 2.4 to 3.6 or from 4.0 to 6.0. Further, suitable examples of HPMC are characterized by a methoxyl substitution of from 28.0 to 30.0, a hydroxypropoxyl substitution of from 7.0 to 12.0, and a loss on drying (weight %) of 5.0% at maximum. HPMC corresponding to the above characteristics is commercially available by Dupont under the tradename Methocel® premium E3 and Methocel® premium E5.
In a preferred embodiment, the coating layer comprises a solid dispersion comprising odevixibat and a film-forming polymer, preferably odevixibat and HPMC.
In one embodiment of the present invention the particles have an average D50 particle size of between about 100 pm and about 1500 pm. Preferably, the particles have an average D50 particle size of between about 500 pm and about 1200 pm in size, more preferably of between about 600 pm and about 800 pm, even more preferably of about 700 pm. The particle size is determined microscopically. Suitable microscopes include a digital microscope, i.e. an optical microscope equipped with a digital camera, such as Keyence VHX-5000 microscope, e.g. equipped with a 200-2000x objective.
As used herein, an “average D50 particle size” refers to the Particle Size Distribution D50, which is also known as the median diameter, and is the value of the particle diameter at 50% in the cumulative distribution. In other words, the portions of particles with diameters smaller and larger than the average D50 particle size are 50%.
In another embodiment of the present invention each particle contains odevixibat in an amount of from about 0.1% w/w to about 5.0% w/w based on the total weight of the particle. Preferably, each particle contains odevixibat in an amount of from about 0.5% w/w to about 2.0% w/w based on the total weight of the particle. In a particularly preferred embodiment each particle contains odevixibat in an amount of about 0.5% w/w based on the total weight of the particle. In another particularly preferred embodiment each particle contains odevixibat in an amount of about 1.5% w/w based on the total weight of the particle.
In one embodiment of the invention the coating layer of the particles has a thickness of between about 1.5 and about 2.5 pm or between about 6.5 and about 7.5 pm. In a preferred embodiment the coating layer of the particles has a thickness of between about 2 and about 3 pm. In another preferred embodiment the coating layer of the particles has a thickness of about 7 pm.
The particles of the present invention can be obtained by spraying the coating layer as a solution of odevixibat, and optionally a film-forming polymer, in a mixture of a water- miscible organic solvent and water onto the particles. In a preferred embodiment, the mixture of a water-miscible organic solvent and water is a mixture of a water-miscible alcohol and water, preferably a mixture of a water-miscible alcohol selected from the group consisting of methanol, ethanol, 1 -propanol and 2-propanol, and water. In a particularly preferred embodiment, the water-miscible alcohol is ethanol.
The mixture of a water-miscible organic solvent and water comprises from about 10% w/w to about 20% w/w, preferably about 13% w/w of a water-miscible organic solvent based on the total weight of the mixture. According to the invention, the solution of odevixibat or a pharmaceutically acceptable salt thereof, and optionally the film-forming polymer, is prepared by (i) dissolving the film-forming polymer (e.g. HPMC) in a mixture of a water-miscible organic solvent and water, (ii) dissolving odevixibat in a mixture of a water-miscible organic solvent and water, and (iii) combining the solutions obtained in step (i) and step (ii).
In a preferred embodiment, the mixture of a water-miscible organic solvent and water is a mixture of a water-miscible alcohol and water, preferably a mixture of a water-miscible alcohol selected from the group consisting of methanol, ethanol, 1 -propanol and 2- propanol, and water. In a particularly preferred embodiment, the water-miscible alcohol is ethanol.
The particles of the invention can be regarded as a pharmaceutical composition, in particular as a multiparticulate pharmaceutical composition. Further, the particles can also be processed into oral dosage forms, particularly an oral dosage form, e.g. filled into capsules or sachets or the particles can be compressed into tablets. These dosage forms also represent pharmaceutical compositions including the particles of the invention.
Therefore, the invention further relates to a pharmaceutical composition and/or to an oral dosage form of odevixibat comprising the particles disclosed herein. In particular, the invention further relates to a pharmaceutical composition and/or to an oral dosage form of odevixibat comprising a plurality of said particles. The pharmaceutical composition can be in the form of a tablet or may constitute a formulation, wherein the particles are contained within a sachet or a capsule. An exemplary capsule is a hard capsule, e.g. containing HPMC and MCC as excipients. The capsules can either be swallowed as a whole or are sprinkled onto food.
A multiparticulate formulation containing low doses of odevixibat is advantageous since such a formulation enables weight-based dosing and may be particularly suitable for administering to paediatric patients. In some embodiments, the pharmaceutical formulation is a paediatric formulation.
The odevixibat-coated particle or the tablet comprising the odevixibat-coated particles may further be coated, e.g. with an enteric coating.
In another embodiment the dosage form of the present invention may contain odevixibat in an amount of from about 0.05% w/w to about 5.0% w/w based on the total weight of the dosage form. Generally, the dosage form of the present invention can contain 0.1 to 5 mg odevixibat, preferably 0.2 to 2 mg, in particular 200 pg, 400 pg, 600 pg or 1200 pg of odevixibat.
The odevixibat-coated particles or the dosage form comprising the odevixibat-coated particles can be used as a medicament. Therefore, the invention further relates to the odevixibat-coated particles described herein or the pharmaceutical compositions or dosage forms comprising the odevixibat-coated particles described herein for use as a medicament.
In one embodiment the odevixibat-coated particles or the pharmaceutical composition or dosage forms comprising the odevixibat-coated particles can be used in the treatment or prevention of a liver disease such as a bile acid-dependent disease, progressive familial intrahepatic cholestasis (PFIC), or biliary atresia.
In another aspect, the invention relates to a process for the preparation of the odevixibat- coated particles disclosed herein.
In particular, the process for the preparation of the odevixibat-coated particles comprises the step of preparing a coating solution of odevixibat in a mixture of a water-miscible organic solvent and water. Therefore, any form of odevixibat including odevixibat in free form or a pharmaceutically acceptable salt thereof, amorphous odevixibat, any crystalline modification of odevixibat or any solvate thereof is simply dissolved in a mixture of a water-miscible organic solvent and water. In a particularly preferred embodiment, odevixibat-2-pentanol solvate is dissolved in a mixture of a water-miscible organic solvent and water.
In a preferred embodiment, the mixture of a water-miscible organic solvent and water is a mixture of a water-miscible alcohol and water, preferably a mixture of a water-miscible alcohol selected from the group consisting of methanol, ethanol, 1 -propanol and 2- propanol, and water. In a particularly preferred embodiment, the water-miscible alcohol is ethanol.
The mixture of a water-miscible organic solvent and water comprises from about 10% w/w to about 20% w/w, preferably 10% w/w to about 15% w/w, e.g. about 13% w/w of a water-miscible organic solvent based on the total weight of the mixture.
In a preferred embodiment, the process for the preparation of odevixibat-coated particles comprises the step of preparing a coating solution of odevixibat and a film-forming polymer in a mixture of a water-miscible organic solvent and water. In particular, the coating solution is prepared by
(i) dissolving the film-forming polymer in a mixture of a water-miscible organic solvent and water;
(ii) dissolving odevixibat in a mixture of a water-miscible organic solvent and water; and
(iii) combining the solutions obtained in step (i) and step (ii).
The film-forming polymer can be any one of those described above. In a preferred embodiment the film-forming polymer is HPMC.
The process for the preparation of the odevixibat-coated particles further comprises the step of spraying the coating solution onto the cores. Thereby, particles comprising a core and a coating layer are obtained, wherein the coating layer comprises odevixibat in a noncrystalline form.
The cores can be any of those described above. In a preferred embodiment the cores are MCC spheres or sugar spheres. A typical process for the coating of MCC or sugar spheres with a film former and a solution of odevixibat is described in the following.
Preparation of the coating solution:
A film-forming polymer (e.g. HPMC) is dissolved in a mixture of a water-miscible organic solvent (e.g. ethanol) and H2O overnight while stirring. The mixture can be a mixture of ethanol (e.g. 13% w/w) and H2O.
Then, odevixibat, preferably in the form of odevixibat-2-pentanol solvate, is dissolved in a mixture of a water-miscible organic solvent (e.g. ethanol) and H2O, preferably in a mixture of ethanol (e.g. 13% w/w) and H2O, and both solutions are combined.
The amount of coating solution used in the process is determined accordingly in order to reach a desired drug load of the particles, for example a final drug load of 0.5% or 1.5% based on the total weight of the particle.
Procedure of the fluidized bed coating process:
In a fluid bed coater with Wurster insert, MCC spheres or sugar spheres are coated using the previously prepared coating solution:
Settings:
Figure imgf000013_0001
The coated spheres are then collected and fractionated by sieving. The fractions >500 pm and <1200 pm are analyzed by XRD (crystallinity), HPLC (drug content) and by microscope (coating thickness).
The invention further relates to odevixibat-coated particles obtainable by the process described herein. For the preparation of the odevixibat-coated particles described herein, odevixibat-2- pentanol-solvate is particularly suitable.
Therefore, the present invention relates in a further aspect to odevixibat-2-pentanol- solvate, particularly to a crystalline form of odevixibat-2-pentanol-solvate, and to a process for its preparation.
Example 29 of WO 2003/022286 yields odevixibat free compound as a “white solid” after preparative HPLC. This material is not crystalline.
WO 2019/245448 describes two polymorphs of odevixibat, modification 1 and modification 2. Modification 1 is a channel hydrate containing up to 2 mol eq. of water. At 30% relative humidity (RH) modification 1 is present as a sesquihydrate containing about 1.5 mol eq. of water. NMR data (1H-NMR) of modification 1 is shown in Figure 2 (upper panel). Modification 2 is a mixed hydrate/solvate and exists as isomorphic solvates. Modification 2 may comprise MeOH, EtOH, 2-PrOH, ACT, ACNL, 1,4-DX, DMF or DMSO. Upon drying, the organic solvent is released and modification 2 transforms to modification 1.
Both modification 1 and modification 2 are thus associated with certain disadvantages. In particular, modification 2 is not stable, and modification l is a variable hydrate containing varying proportions of water, which is likely to result in problems with regard to content uniformity.
In one embodiment, the present invention relates to a crystalline form of odevixibat 2- pentanol solvate. The novel crystalline solvate can be obtained by crystallization of odevixibat (e.g. obtained according to WO 2003/022286, example 29) from 2-pentanol. Odevixibat 2-pentanol solvate according to the invention preferably contains approximately 1 mol eq. 2-pentanol, as determined by nuclear magnetic resonance (NMR). NMR data (1H-NMR) of odevixibat 2-pentanol solvate is shown in Figure 2 (middle panel).
In particular, the present invention relates to a crystalline form of odevixibat 2-pentanol solvate characterized by having an X-ray powder diffraction (XRPD) pattern [powder X- ray diffractogram - PXRD] comprising reflections at 2-Theta angles of (4.6 ± 0.2)°, (5.6 ± 0.2)°, (6.6 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphal,2 radiation having a wavelength of 0.15419 nm (Figure 3). More particularly, the present invention relates to a crystalline form of odevixibat 2- pentanol solvate characterized by having an X-ray powder diffraction (XRPD) pattern [powder X-ray diffractogram - PXRD] comprising reflections at 2-Theta angles of (4.6 ± 0.2)°, (5.6 ± 0.2)°, (6.6 ± 0.2)°, (7.0 ± 0.2)°, (8.7 ± 0.2)°, (10.5 ± 0.2)°, (18.1 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)°, (22.7 ± 0.2)°, (23.4 ± 0.2)°, (24.2 ± 0.2)°, (24.9 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphal,2 radiation having a wavelength of 0.15419 nm (Figure 3).
More particularly, the present invention relates to a crystalline form of odevixibat 2- pentanol solvate characterized by having an X-ray powder diffraction (XRPD) pattern [powder X-ray diffractogram - PXRD] comprising reflections at 2-Theta angles of (4.6 ± 0.2)°, (5.6 ± 0.2)°, (6.6 ± 0.2)°, (7.0 ± 0.2)°, (8.4 ± 0.2)°, (8.7 ± 0.2)°, (9.1 ± 0.2)°, (9.3 ± 0.2)°, (10.5 ± 0.2)°, (11.2 ± 0.2)°, (11.5 ± 0.2)°, (11.7 ± 0.2)°, (12.1 ± 0.2)°, (13.0 ± 0.2)°, (13.3 ± 0.2)°, (13.8 ± 0.2)°, (14.2 ± 0.2)°, (14.5 ± 0.2)°, (15.5 ± 0.2)°, (16.2 ± 0.2)°, (16.8 ± 0.2)°, (17.2 ± 0.2)°, (17.9 ± 0.2)°, (18.1 ± 0.2)°, (18.2 ± 0.2)°, (19.1 ± 0.2)°, (19.4 ± 0.2)°, (19.6 ± 0.2)°, (20.2 ± 0.2)°, (20.4 ± 0.2)°, (20.7 ± 0.2)°, (21.2 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)°, (22.7 ± 0.2)°, (23.4 ± 0.2)°, (24.2 ± 0.2)°, (24.9 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphal,2 radiation having a wavelength of 0.15419 nm (Figure 3).
The invention further relates to a process for the preparation of odevixibat-2-pentanol solvate comprising:
(i) providing a suspension of odevixibat in 2-pentanol;
(ii) heating the suspension to form a clear solution; and
(iii) crystallizing odevixibat-2-pentanol solvate as defined herein from the solution obtained in step (ii).
The invention further relates to odevixibat 2-pentanol solvate obtainable by the process described herein.
Another subject of the present invention is the use of odevixibat-2-pentanol solvate for preparing odevixibat in non-crystalline form, in particular the use for preparing odevixibiat in form of a solid dispersion.
In a preferred embodiment, odevixibat-2-pentanol solvate is suitable for the preparation of odevixibat-coated particles using the process described herein. In particular, odevixibat-2-pentanol solvate is suitable for the preparation of odevixibat-coated particles using the process for coating of MCC and sugar spheres with a solution of odevixibat and HPMC as film-forming polymer.
Thus, in one embodiment, the invention relates to the use of odevixibat-2-pentanol solvate as described herein or to the use of odevixibat-2-pentanol solvate obtained by the process described herein for the manufacture of particles containing odevixibat in non-crystalline form.
Said particles comprising odevixibat in non-crystalline form are particularly suitable for the treatment of a liver disease.
The present invention further relates to the use of the particles described herein for the manufacture of a medicament for the treatment of a liver disease, e.g. such as bile aciddependent liver diseases, and particularly cholestatic liver diseases such as biliary atresia, progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome (ALGS) and paediatric cholestatic pruritus.
The present invention further relates to a method of treating or preventing a liver disease, comprising administering a therapeutically effective amount of the particles described herein or the pharmaceutical composition described herein to a patient in need of such treatment.
EXAMPLES
Example 1
Preparation of a crystalline form of odevixibat-2-pentanol solvate
3,988 g of odevixibat were suspended at room temperature in 40 ml of 2-pentanol. The suspension was heated to 75°C to form a clear solution. The mixture was allowed to cool naturally and seeds were added at 62°C during stirring. The resulting suspension was allowed to stir over night at room temperature. The solid material was filtered and dried under vacuum at room temperature to yield 4,097 g odevixibat-2-pentanol solvate as a white solid. The resulting material was characterized by PXRD (Figure 3), IR (Figure 4) and DSC (Figure 5). Powder X-ray diffraction (Figure 3):
Powder X-ray diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphal,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector. Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40 s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions. A typical precision of the 2- Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta.
The reflection list of crystalline form of odevixibat-2-pentanol solvate of the present invention is provided in Table 1 below.
Table 1 :
Figure imgf000017_0001
Figure imgf000018_0001
Reflection positions of crystalline odevixibat 2-pentanol in the range of from 2 to 30° 2- Theta; a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2- Theta.
Fourier transform infrared spectroscopy (Figure 4): The crystalline odevixibat-2-pentanol solvate according to the present invention was investigated by FTIR spectroscopy. The FTIR spectrum was recorded (obtained) on a MKII Golden Gate™ Single Reflection Diamond ATR cell with a Bruker Tensor 27 FTIR spectrometer with 4 cm'1 resolution at RT. To record a spectrum a spatula tip of the sample was applied to the surface of the diamond in powder form. Then the sample was pressed onto the diamond with a sapphire anvil and the spectrum was recorded. A spectrum of the clean diamond was used as background spectrum. A typical precision of the wavenumber values is in the range of from about ± 2 cm'1. A representative FTIR
16 spectrum of the crystalline odevixibat-2-pentanol solvate according to the present invention is displayed and the corresponding peak list is provided in Table 2 below.
Table 2:
Figure imgf000019_0001
Differential scanning calorimetry (DSC) (Figure 5):
The crystalline form of odevixibat-2-pentanol solvate was investigated by DSC, which was performed on a Mettler Polymer DSC R instrument. The sample (4.25 mg) was heated in a 40 microliter aluminium pan with a pierced aluminium lid from 25 to 120°C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.
The DSC curve (see Figure 5) of the crystalline odevixibat-2-pentanol of the present invention shows an endotherm with an onset temperature of about 93°C, which is due to a melting process.
Example 2
Odevixibat-coated MCC spheres (final 0.5% drug load)
Procedure for the preparation of the coating solution:
1.4 g HPMC (Methocel® premium E5) was dissolved in a mixture of 15.75 g EtOH and 2.35 g H2O (corresponds to 13% w/w) overnight while stirring. Then 0.45 g odevixibat (77% purity) was dissolved in a mixture of 3.05 g EtOH and 0.46 g H2O and both solutions were combined.
Procedure of the coating process:
In a Mini Glatt, 70 g MCC spheres (Vivapur® MCC sphere 700) were coated in a fluidized bed coater with Wurster insert using the previously prepared coating solution, aiming a final 0.5% drug load.
Settings Mini Glatt:
Figure imgf000020_0001
The coated spheres were then collected and fractionated by sieving. The fraction >500 pm and <1200 pm was weighted, resulting in 69.6 g (97% yield) and over 90% API recovery (determined by HPLC). XRD confirmed no crystalline reflexes. A coating thickness of 2-3 pm was determined using a Keyence VHX-5000 microscope equipped with a Keyence VHX-5020 camera.
Example 3
Odevixibat-coated MCC spheres (final 1.5% drug load)
Procedure for the preparation of the coating solution:
4.2 g HPMC (Methocel® premium E5) was dissolved in a mixture of 45.92 g EtOH and 7.03 g H2O (corresponds to 13% w/w) overnight while stirring. Then 1.05 g odevixibat (98% purity) was dissolved in a mixture of 3.05 g EtOH and 0.46 g H2O and both solutions were combined. Glassware was washed with 5 mL EtOH/H2O (13% w/w).
Procedure of the coating process:
In a Mini Glatt, 70 g MCC spheres (Vivapur® MCC sphere 700) were coated in a fluidized bed coater with Wurster insert using the previously prepared coating solution, aiming a final 1.5% drug load
Settings Mini Glatt:
Figure imgf000021_0001
The coated spheres were then collected and fractionated by sieving. The fraction >500 pm and <1200 pm was weighted, resulting in 58.5 g (78% yield) and over 90% API recovery (determined by HPLC). XRD confirmed no crystalline reflexes. A coating thickness of 7 pm was determined using a Keyence VHX-5000 microscope equipped with a Keyence VHX-5020 camera. Example 4
Odevixibat-coated sugar spheres (final 0.5% drug load)
Procedure for the preparation of the coating solution:
4.2 g HPMC (Methocel® premium E5) was dissolved in a mixture of 45.92 g EtOH and 7.03 g H2O (corresponds to 13% w/w) overnight while stirring. Then 0.35 g odevixibat (98% purity) was dissolved in a mixture of 3.05 g EtOH and 0.46 g H2O and both solutions were combined. Glassware was washed with 5 mL EtOH/H2O (13% w/w).
Procedure of the coating process using sugar spheres:
In a Mini Glatt, 70 g sugar spheres (Vivapharm® 20-25) were coated in a fluidized bed coater with Wurster insert using the previously prepared coating solution, aiming a final 0.5% drug load
Settings Mini Glatt:
Figure imgf000022_0001
The coated spheres were then collected and fractionated by sieving. The fraction >500 pm and <1200 pm were weighted, resulting in 70.0 g (98% yield) and over 90% API recovery (determined by HPLC). XRD confirmed no crystalline reflexes.
Example 5 (Reference Example)
Odevixibat-coated MCC spheres (final 0.5% drug load)
Microcrystalline cellulose spheres were coated with a coating suspension of odevixibat comprising 1500 g/batch microcrystalline cellulose spheres 700 (Vivapur® MCC sphere 700), 7.5 g/batch odevixibat, 30 g/batch hypromellose 3 mPa.s (Methocel® E3 premium) and 337.5 g/batch purified water to obtain particles containing 0.5% w/w odevixibat. Crystalline odevixibat was used.
In the process water was used as single solvent and therefore a suspension of odevixibat (modification 1) was performed according to WO 2019/245449 Al in the Mini Glatt using following settings:
Figure imgf000023_0001
Yield was determined as 96.2% (<500 pm and >1200 pm) with over 90% API recovery (HPLC). Coating thickness of 2-3 pm was measured using a Keyence VHX-5000 microscope equipped with a Keyence VHX-5020 camera. XRD analysis confirmed the presence of crystalline odevixibat (modification 1).

Claims

Claims Particles comprising a core and a coating layer, wherein the coating layer comprises odevixibat in a non-crystalline form. The particles of claim 1, wherein odevixibat is amorphous or in a solid dispersion. The particles of claim 1 or claim 2, wherein the coating layer further comprises a filmforming polymer. The particles of any one of the preceding claims, wherein the coating layer comprises a solid dispersion comprising odevixibat and HPMC. The particles of any one of the preceding claims, wherein the core comprises microcrystalline cellulose or sucrose. The particles of any one of the preceding claims, wherein each particle contains odevixibat in an amount of from about 0.1% w/w to about 5.0% w/w based on the total weight of the particle. The particles of any one of the preceding claims, wherein the coating layer has a thickness of between about 1.5 to about 2.5 pm or between about 6.5 to about 7.5 pm. Process for the preparation of the particles of any one of claims 1 to 7, the process comprising the step of preparing a coating solution of odevixibat, and optionally a filmforming polymer, in a mixture of a water-miscible organic solvent and water. The process of claim 8, wherein the coating solution comprises a mixture of a water- miscible alcohol and water, preferably wherein the coating solution comprises a mixture of a water-miscible alcohol selected from the group consisting of methanol, ethanol, 1- propanol and 2-propanol or any mixture thereof, and water. The process of claim 8 or claim 9, wherein the coating solution is prepared by
(i) dissolving the film-forming polymer in a mixture of a water-miscible organic solvent and water;
(ii) dissolving odevixibat in a mixture of a water-miscible organic solvent and water; and
(iii) combining the solutions obtained in step (i) and step (ii). The process of any one of claims 8 to 10, wherein odevixibat is used in form of odevixibat-2-pentanol solvate. Odevixibat-2-pentanol solvate. Use of odevixibat-2 -pentanol solvate for preparing odevixibat in non-crystalline form. Oral dosage form of odevixibat comprising the particles of any one of claims 1 to 7 or comprising the particles prepared by the process according to any one of claims 8 to 11. The particles of any one of claims 1 to 7 or the particles prepared by the process according to any one of claims 8 to 11 or the oral dosage form of odevixibat according to claim 14 for use as a medicament, preferably for use in the treatment or prevention of a liver disease.
PCT/EP2023/056485 2022-03-16 2023-03-14 Particles comprising non-crystalline odevixibat WO2023174937A1 (en)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2003022286A1 (en) 2001-09-08 2003-03-20 Astrazeneca Ab Benzothiazepine and benzothiadiazepine derivatives with ileal bile acid transport (ibat) inhibitory activity for the treatment hyperlipidaemia
WO2012064266A1 (en) 2010-11-08 2012-05-18 Albireo Ab Ibat inhibitors for the treatment of liver diseases
WO2019245449A1 (en) 2018-06-20 2019-12-26 Albireo Ab Pharmaceutical formulation of odevixibat

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Publication number Priority date Publication date Assignee Title
WO2003022286A1 (en) 2001-09-08 2003-03-20 Astrazeneca Ab Benzothiazepine and benzothiadiazepine derivatives with ileal bile acid transport (ibat) inhibitory activity for the treatment hyperlipidaemia
WO2012064266A1 (en) 2010-11-08 2012-05-18 Albireo Ab Ibat inhibitors for the treatment of liver diseases
WO2019245449A1 (en) 2018-06-20 2019-12-26 Albireo Ab Pharmaceutical formulation of odevixibat
WO2019245448A1 (en) 2018-06-20 2019-12-26 Albireo Ab Crystal modifications of odevixibat

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MENDONSA NICOLE ET AL: "Manufacturing strategies to develop amorphous solid dispersions: An overview", JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY, vol. 55, 1 February 2020 (2020-02-01), FR, XP055913539, ISSN: 1773-2247, DOI: 10.1016/j.jddst.2019.101459 *
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