Pharmaceutical composition containing Akt protein kinase inhibitor

Abstract

The present invention relates to a pharmaceutical composition comprising an Akt protein kinase inhibitor having therapeutic activity against diseases such as cancer and to a method for its preparation and use as a medicament.

Description

[0001] This application is a divisional application of the invention application with the application date of August 9, 2017, the Chinese application number of 201780061307.4, and the invention name of “Pharmaceutical composition containing Akt protein kinase inhibitor”. Technical Field

[0002] The present invention relates to a pharmaceutical composition comprising an Akt protein kinase inhibitor having therapeutic activity against diseases such as cancer and to a method for its preparation and use as a medicament. Background Art

[0003] Protein kinase B (PKB), also known as Akt, is a serine / threonine kinase that is overexpressed in certain human tumors. International patent application WO 2008 / 006040 (A1) and U.S. Patent No. 8,063,050 (B2) discuss a variety of Akt inhibitors, including the compound (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one, whose INN recommended name is ipatasertib (WHO Drug Information Volume 27, Issue 3, 2013, Recommended INN: List 70), which is undergoing clinical trials for the treatment of various cancers.

[0004]

[0005] Stable, effective and convenient pharmaceutical compositions require active pharmaceutical ingredients. The present invention provides a pharmaceutical composition comprising an Akt inhibitor, particularly etanercept or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0006] So far, only very few crystalline forms of etaserti have been described. For example, WO 2013 / 173784 A1 describes crystalline benzenesulfonate and toluenesulfonate salts of etaserti. Benzenesulfonic acid and p-toluenesulfonic acid are both less preferred anions for pharmaceutically acceptable salts.

[0007] The best pharmaceutically acceptable solid form of etaserti described to date is the amorphous anhydrous monohydrochloride salt as described, for example, in WO 2013 / 173811 A1.

[0008] It has been found that etaserti monohydrochloride exhibits unique mechanical properties involving high brittle deformation characteristics (3 times more brittle than lactose), making it very difficult to process by mechanical compression. During the tableting of conventional pharmaceutical compositions containing etaserti, mechanical compression leads to exhausted compressibility, followed by elastic recovery of the tablets upon decompression. Therefore, conventional pharmaceutical compositions containing etaserti monohydrochloride are not suitable for direct compression due to the problem of fragmentation (cracks formed during decompression), which can be detected as small cracks and breaks in the tablet core (e.g. using X-ray microtomography). High-speed tableting methods required in industry may not be achievable.

[0009] It has been found that etaserti has a very high solubility (>1 g / g water; >2 g / g water / ethanol 1:1) and a very high hygroscopicity (about 6% at 50% RH, >35% at 95% RH). Although poor solubility is often a limiting factor in the development of galenical formulations of other APIs (active pharmaceutical ingredients), high solubility can also cause problems for process performance. Due to this very high inherent hygroscopicity of the API, the etaserti drug substance tends to automatically dissolve into a honey-like viscous liquid when humidity increases. This high solubility and hygroscopicity can cause serious problems for processing as well as stability and shelf life of the final product. Therefore, conventional pharmaceutical compositions comprising etaserti and methods for preparing pharmaceutical compositions comprising wetting (e.g., wet granulation) are difficult to achieve due to the high solubility and high hygroscopicity of the API.

[0010] It was further found that alternative granulation methods for etaserti (such as high shear methods of continuous wetting and drying) are difficult to control, do not produce a consistently high quality product and require large amounts of hygroscopic agents (at least 10% wt-15% wt).

[0011] Due to the high solubility and hygroscopicity of etaserti, conventional methods for preparing amorphous etaserti monohydrochloride require long drying times at high temperatures and must remove pharmaceutically less preferred solvents that may cause partial crystallization. Conventional methods for preparing amorphous etaserti monohydrochloride are not suitable for providing a homogeneous, amorphous and stable API that exhibits particle properties suitable for use in a formulation method without further adjustment or reprocessing. Therefore, there is a need for an improved method for preparing amorphous etaserti monohydrochloride that is easy to use in the preparation of pharmaceutical compositions. Summary of the invention

[0012] The present invention provides a pharmaceutical composition comprising etanercept and a method for producing the same, wherein the above-mentioned problems have been solved.

[0013] The inventors of the present invention have found that a pharmaceutical composition comprising etaserti and a certain amount of intragranular material having plastic deformation properties can prevent the formation of brittle cracks during compression. Therefore, a tablet core comprising etaserti and a pharmaceutically acceptable excipient having plastic deformation characteristics significantly improves processability.

[0014] The inventors of the present invention have found that a pharmaceutical composition comprising eltaserti and a certain amount of an intragranular hygroscopic agent can prevent processing problems when eltaserti dissolves during granulation. Therefore, a pharmaceutical composition comprising eltaserti and a certain amount of an intragranular hygroscopic agent significantly improves processability.

[0015] The inventors of the present invention surprisingly found that fluidized bed granulation is a well-controllable process suitable for providing granules comprising etanercept of high and constant quality.

[0016] As mentioned above, the only solid form of etaserti suitable for drug development and manufacturing known to date is the amorphous anhydrous monohydrochloride salt (etaserti·HCl).

[0017] It has been found that conventional drying methods for etanercept produce only moderate results due to the high solubility and hygroscopicity of the API and the desolvation of the complex. Long drying times at high temperatures and forced removal of pharmaceutically less preferred or even unacceptable solvents are required to comply with the standards of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). In addition, conventional drying methods produce a mixture of amorphous and partially crystalline materials.

[0018] The ethyl acetate monosolvate of etaserti monohydrochloride has a defined stoichiometry, which contains one ethyl acetate molecule per etaserti molecule. By conventional drying methods, the amount of ethyl acetate per etaserti in the ethyl acetate monosolvate of etaserti monohydrochloride can be reduced to a residual solvent content of 2% wt to 10% wt of ethyl acetate, typically 5% wt to 7% wt of ethyl acetate. Further reduction of the ethyl acetate content, for example below 0.5% wt, can only be achieved by harsh and prolonged drying conditions.

[0019] Aptashertib monohydrochloride is obtained from aptashertib monohydrochloride ethyl acetate. It has now been discovered that water is a key driver for the conversion of aptashertib·HCl·EtOAc to amorphous aptashertib·HCl.

[0020] The use of vacuum drying and humidified nitrogen in a conical screw dryer for drying / wetting cycles allowed the removal of EtOAc and the amorphous conversion to be achieved. However, the drying time was not significantly improved - it still takes several days to complete a conventional batch on an industrial scale. In addition, solid-state changes were observed in the XRPD pattern. Further particle size distribution could not be controlled, resulting in only inconsistent particle size distribution curves.

[0021] WO 2013 / 173811 A1 discloses the production of amorphous etanercept monohydrochloride by spray drying (Examples 12A-C,

[00138] ) using a two-fluid nozzle spray dryer. It has been found that the spray drying methods described in the prior art produce only moderate results in terms of particle size and particle shape, i.e. a bimodal particle size distribution with a large number of submicron particles is obtained. Therefore, the flowability and processability of the material thus obtained are very limited.

[0022] The present invention further provides an improved spray drying process for producing amorphous etaserti HCl, particularly etaserti solvate, most particularly etaserti HCl .EtOAc from solid etaserti without the use of problematic solvents, which produces a chemically stable homogeneous amorphous material having improved flowability, bulk density, particle shape and particle size distribution, which can be used for application in the method for producing the pharmaceutical composition disclosed herein without the need for additional treatment, conditioning or reprocessing. The product obtained in the process of the present invention produces a consistent and robust quality between batches.

[0023] Surprisingly, it was found that spray drying with water as solvent produced particularly beneficial results because etaserti has been found not to form hydrates or other crystalline forms with water, because the high solubility of etaserti in water allows for high API concentrations, and because water is considered safe in contrast to many organic solvents.

[0024] It was found that the spray drying process using a rotary wheel atomizer as described in the Examples can provide amorphous etanercept HCl with a purity as high as >99.4%.

[0025] The spray drying process of the present invention using a rotary wheel atomizer as described in the Examples offers the advantage that both residual EtOAc and water are controlled immediately - no post drying is required to reach ICH Q3C (R5) limits.

[0026] The material obtained in the spray drying process of the present invention using a rotating wheel atomizer shows excellent powder properties based on flow behavior, PSD curves and SEM images.

[0027] Due to the increased particle size of the material obtained in the spray drying process of the present invention compared to materials obtained by conventional methods, the processability of the API is improved and the disintegration of tablets containing the material is improved.

[0028] The bulk density of the material obtained in the spray drying method of the present invention using a rotary wheel atomizer is increased by nearly 2 times relative to the material obtained in other conventional methods. The bulk density has a very high influence, for example, on the subsequent tableting process. DETAILED DESCRIPTION

[0029] The term "etashertib·HCl·EtOAc" as used herein refers to etashertib monohydrochloride containing ethyl acetate in the crystal lattice, particularly containing greater than 0.5% wt of ethyl acetate in the crystal lattice, more particularly containing greater than 2% wt of ethyl acetate in the crystal lattice, and most particularly containing greater than 5% wt of ethyl acetate in the crystal lattice.

[0030] The term "tablet flakes" means that (parts of) the tablet separate into two or more distinct layers. Flakes can be caused by air entrapment during compression and subsequent expulsion during tableting or by over-compression, causing the particles to deform and no longer lock together. Flakes can also occur when fine and light particles do not lock together.

[0031] The indication "% wt" denotes the mass percentage based on the total weight of the tablet core (or, if indicated, on the total weight of the final film-coated tablet).

[0032] A "fluidized bed" occurs when a quantity of solid particles is placed under appropriate conditions so that the mixture behaves as a fluid. This is usually done by forcing pressurized air, gas or other fluid through a bed of solid particles. This causes the solid medium to acquire properties and attributes similar to a normal fluid, resulting in what is known as fluidization. Fluidized beds are commonly used in the pharmaceutical industry to dry, granulate and coat any number of different active pharmaceutical ingredients (APIs), excipients or other formulations.

[0033] The "fluidized bed granulation" process involves suspending the particles in an air stream (i.e., fluidized granulation) and spraying a liquid onto the fluidized bed, either from the top of the system downward (top spray granulator) or from the bottom up (bottom spray granulator or Wurster process) into the fluidized bed. The particles in the spray path become slightly wet and sticky. The sticky particles collide with other particles in the material bed and adhere to them to form granules. There are two different modes of fluidized bed granulation: wet stage and dry stage. In dry stage granulation, the particles only need to be slightly wetted to become sticky and adhere to each other. The granulating solution is applied at a rate less than or equal to its evaporation rate. Therefore, the particles remain "dry" throughout the process.

[0034] In wet granulation, the granules require a large amount of moisture or granulating solution to become sticky enough to adhere to each other. The granulating solution is applied at a rate higher than the evaporation rate until the granules accumulate enough moisture to granulate. Note: The properties of the granules when wet and the type of granulating solution used will determine which granulation method is most appropriate. Although dry stage is more common, wet stage granulation can achieve a denser product. The specific fluidized bed granulator of the present invention is a top spray granulator in dry stage mode.

[0035] The terms "atomization" and "gasification" both refer to the process of preparing an aerosol, ie a dispersion of solid particles or liquid droplets in a gas, especially a colloidal dispersion.

[0036] The term "aqueous mist" refers to an aerosol comprising small water droplets (less than 10 μm in diameter, particularly less than 5 μm, most particularly less than 1 μm) suspended in a gas, particularly in air or nitrogen, most particularly in nitrogen.

[0037] The term "atomizer" means a device that promotes the atomization of a dispersion of solid particles or liquid droplets into an aerosol. Atomizers and their use are described, for example, in Nasr, GG et al., Industrial Sprays and Atomization: Design, Analysis and Applications, Springer, 2002, ISBN 978-1852334604.

[0038] Nebulizers can be classified based on the energy input used to cause atomization (breaking the fluid into droplets). Nebulizers include:

[0039] ●Single-fluid nozzles, such as flat nozzles, formed hole nozzles, surface impact single-fluid nozzles, pressure swirl single-fluid nozzles, solid cone single-fluid nozzles and compound nozzles;

[0040] ● Two-fluid nozzles, such as internal mixing two-fluid nozzles and external mixing two-fluid nozzles;

[0041] ●Rotary atomizer;

[0042] Ultrasonic nebulizer;

[0043] ●Electrostatic atomizer.

[0044] Specific atomizers of the present invention are two-fluid nozzles and rotary atomizers. Most specific atomizers of the present invention are rotary atomizers.

[0045] The term "rotating wheel atomizer", also called "rotating wheel atomizer" or "rotary atomizer" refers to a device for atomization in which the feed is centrifugally accelerated to high speed in the atomizer. The degree of atomization depends on the peripheral speed, feed rate, liquid properties and atomizer wheel design.

[0046] The term "rotating wheel spray dryer", also called "rotating wheel spray dryer" or "rotary spray dryer" refers to a device comprising a rotary atomizer. A rotary spray dryer is used for atomization and drying, wherein the feed is centrifugally accelerated to high speed in the atomizer wheel and then discharged into a hot drying gas. The degree of atomization and the particle morphology depend on the peripheral speed, the feed rate, the liquid properties and the atomizer wheel design. The particle size is adjusted by varying the peripheral speed. A specific rotary wheel spray dryer comprises 24 holes.

[0047] The term "two-fluid nozzle" or "two-fluid nozzle atomizer" refers to a device for atomization in which atomization is achieved pneumatically by a high velocity compressed gas, such as air or nitrogen, especially nitrogen, to affect a liquid feed.

[0048] The term "two-fluid nozzle spray dryer" refers to an apparatus for atomization and drying in which atomization is achieved pneumatically by a high velocity compressed gas (e.g. air or nitrogen, particularly nitrogen) to affect a liquid feed. Particle size is controlled by varying the nozzle flow ratio between atomizing gas and feed. A two-fluid nozzle spray dryer can be operated in a) co-current mode or b) fountain (countercurrent) mode.

[0049] a) When operating in co-current mode, the atomizing material and the drying gas flow in the same direction and the nozzle tip is close to the outlet of the ceiling gas diffuser. Select co-current mode when drying heat-sensitive products.

[0050] b) In fountain or counter-flow mode, the flow directions of the atomizing material and the drying gas are opposite. When coarse particles of non-heat-sensitive feed are required, the two-fluid nozzle in fountain mode is suitable.

[0051] Two-fluid nozzles can be further divided into 1) internal mixing two-fluid nozzles and 2) external mixing two-fluid nozzles, depending on the mixing point of the gas and liquid streams relative to the nozzle face.

[0052] 1) Internal mixing two-fluid nozzles contact the fluid inside the nozzle. The shear between the high-velocity gas and the low-velocity liquid breaks the liquid stream into droplets, producing a high-velocity spray. This type of nozzle tends to use less atomizing gas than an external mixing atomizer and is better suited for higher viscosity streams.

[0053] 2) External mixing two-fluid nozzles (or external mixing two-fluid nozzles) contact the fluid outside the nozzle. This type of nozzle may require more atomizing air and a higher atomizing air pressure drop because the mixing and atomization of the liquid occurs outside the nozzle. For this type of nozzle, the liquid pressure drop is lower and sometimes the liquid is sucked into the nozzle due to the suction caused by the atomizing air nozzle (siphon nozzle).

[0054] The term "single fluid nozzle spray dryer" or "pressure nozzle spray dryer" refers to a device used for atomization and drying, in which atomization is the result of the conversion of pressure energy within the liquid feed into the kinetic energy of the flowing liquid sheet. There is no compressed atomizing gas. The pressure applied to the liquid in the nozzle forces the liquid out of the orifice to produce atomization. The pressure nozzle can be operated in co-current mode or fountain mode. The particle size is adjusted by varying the feed pressure and nozzle size. Pressure nozzles generally provide a narrower particle size distribution and coarser particles than other atomizer types. The choice of nozzle type depends on the feed characteristics and powder specifications.

[0055] The term "cyclonic separation" refers to separation by vortex, i.e., a filter-free method of removing solid particles from a gas or liquid stream by the effects of rotation and gravity. A high-speed rotating flow is established inside a cylindrical or conical container called a cyclone. The flow flows in a spiral, starting at the top (wide end) of the cyclone and ending at the bottom (narrow) end before exiting the cyclone. The denser particles in the rotating flow have too much inertia to follow the tight curve of the flow and strike the outer wall and then fall to the bottom of the cyclone where they can be removed.

[0056] In a conical system, as the rotating flow moves toward the narrow end of the cyclone, the rotation radius of the flow decreases, separating smaller and smaller particles. The cyclone geometry, together with the flow velocity, defines the cut point of the cyclone. This is the size of the particle that will be removed from the flow with 50% efficiency. Particles larger than the cut point will be removed with greater efficiency, while smaller particles will be removed with less efficiency.

[0057] The term "solid form" or "form" is a general term referring to crystalline and / or amorphous forms of a solid material.

[0058] The terms "crystalline form" and "crystal form" are used interchangeably to refer to polymorphs and pseudopolymorphs of a crystalline solid.

[0059] The terms "polymorph" and "modification" may be used synonymously to refer to one particular crystal structure in which a compound can crystallize. Different polymorphs have different arrangements or conformations of the molecules in the crystal lattice, but all have the same elemental composition.

[0060] The term "polymorphism" refers to the ability of a compound to form more than one polymorphic form.

[0061] The terms "solvate" and "pseudopolymorph" may be used synonymously to refer to a crystal having a stoichiometric or non-stoichiometric amount of a solvent incorporated in the crystal lattice. If the incorporated solvent is water, the solvate formed is a "hydrate." When the incorporated solvent is an alcohol, the solvate formed is an "alcoholate."

[0062] The term "salt" refers to a material composed of two components, an acid and a base, wherein the stoichiometric ratio of the two salt formers is well defined. Salt crystals are formed by ionic bonding interactions with complete transfer of hydrogen ions between the acid and the base.

[0063] The term "agglomerate" refers to a collection of primary particles rigidly connected together by fusion, sintering or growth. Agglomerates are not easily dispersed. The term "agglomeration" refers to the process of connecting primary particles together to form agglomerates.

[0064] The term "aggregate" means a collection of primary particles that are loosely attached to each other by contact. Aggregates can be easily dispersed. The term "aggregation" means the process by which primary particles attach to each other to form aggregates.

[0065] The term "amorphous form" refers to a solid material that does not have a distinguishable lattice, and the molecular arrangement of the molecules lacks long-range order. Specifically, amorphous refers to a material that does not show sharp Bragg diffraction peaks. Bragg's law describes the diffraction of crystalline materials with the equation "2d·sin(θ)=n·λ", where "d" represents the vertical distance (in angstroms) between adjacent pairs of planes in the crystal ("d-spacing"), "θ" represents the Bragg angle, "λ" represents the wavelength, and "n" represents an integer. When Bragg's law is met, the reflected light beams are in phase and constructively interfere, so that Bragg diffraction peaks are observed in the X-ray diffraction pattern. At incident angles other than the Bragg angle, the reflected light beams are out of phase and destructive interference or elimination occurs. Amorphous materials do not meet Bragg's law, and sharp Bragg diffraction peaks are not observed in the X-ray diffraction pattern. The XRPD pattern of an amorphous material is also characterized by one or more amorphous halos.

[0066] The term "XRPD" means an analytical method of X-ray powder diffraction. The repeatability of the angle values ​​is within the range of 2θ ± 0.2°, more specifically within the range of 2θ ± 0.1°. The term "approximately" given in combination with the angle value means a variation within the range of 2θ ± 0.2°, in particular within the range of 2θ ± 0.1°. The relative XRPD peak intensity depends on a variety of factors, such as structural factors, temperature factors, crystallinity, polarization factors, multiplicity and Lorentz factors. Due to preferred orientation effects, the relative intensity may vary greatly between measurements. According to USP 941 (US Pharmacopoeia, 37th Edition, General Chapter 941), the relative intensity between two samples of the same material can vary significantly due to the "preferred orientation" effect. Anisotropic materials with preferred orientation will result in anisotropic distributions of properties such as modulus, strength, ductility, toughness, conductivity, thermal expansion, etc., as described, for example, in Kocks UF et al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effect on Materials Properties, Cambridge University Press, 2000). In XRPD as well as Raman spectroscopy, the preferred orientation causes a change in the intensity distribution. The preferred orientation effect is particularly pronounced with relatively large particle size crystalline APIs.

[0067] The term "d 50 The terms "d(0.5)-value" (sometimes also referred to as "d(0.5)-value") and "mass median diameter" (or MMD) are used interchangeably and represent the average particle size by mass, i.e., the average equivalent diameter of the particles, defined as the average particle size in which 50% (w) of the total particles have a larger equivalent spherical diameter and the remaining 50% (w) have a smaller equivalent spherical diameter. Similarly, the term "d 10 The term "d value" refers to the particle size where 10% (w) of the total particles have a smaller equivalent spherical diameter. Similarly, the term "d 90 The "value" represents the particle size where 90% (w) of the total particles have a smaller equivalent spherical diameter.

[0068] The mass-based particle size distribution (PSD) by sieve analysis (also known as graded sieve test) is a widely used classification method for determining particle size and particle size distribution. The mass of the material retained on a specific sieve (usually a mesh size of 50 μm to 800 μm, with a step size of 20 μm to 200 μm) is weighted and expressed as a percentage of the total sampled material (i.e., the cumulative percentage of the weight of particles with a size less than the corresponding sieve). Thus, a mass-based PSD is generated.

[0069] The "characteristic particle size" (d') value obtained by sieve analysis corresponds to the virtual sieve opening size at which 63.2% by weight of the total sieved material passes through the sieve.

[0070] The term yield "as / is" denotes the yield without correction, for example to take into account the amount of solvent in the crystals, ie based on the amount of etaserti.HCl.EtOAc initially used.

[0071] The term yield "corrected" refers to the yield relative to the initial solid (anhydrous etanercept·HCl) on a dry basis.

[0072] The term "anhydrous" as used herein refers to a solid form that has no water or other solvate molecules in the crystal lattice.

[0073] The terms "screening" and "sieving" both refer to the process of reducing particles by size by mechanically induced reduction through a sieve. This process is often called grinding or deagglomeration.

[0074] Active Pharmaceutical Ingredients (API)

[0075] (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etaserti) was found to be a safe, potent and effective Akt inhibitor suitable for the treatment of hyperproliferative diseases such as cancer. A dosage strength of 100 mg or 200 mg of etaserti free base has been found to be optimal for achieving the desired efficacy for different clinical indications.

[0076] In a specific embodiment of the present invention, the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etaserti) or a pharmaceutically acceptable salt thereof.

[0077] In a specific embodiment of the present invention, the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etasertid) or a pharmaceutically acceptable salt thereof in an amorphous form.

[0078] In a specific embodiment of the invention, the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etasertid) as a free base.

[0079] In a specific embodiment of the invention, the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one as the monohydrochloride salt (etaserti HCl).

[0080] In a specific embodiment of the invention, the Akt inhibitor is anhydrous (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etaserti).

[0081] In a specific embodiment of the invention, the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one, in anhydrous form, the monohydrochloride salt (etaserti·HCl).

[0082] In a specific embodiment of the invention, the Akt inhibitor is anhydrous (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one in anhydrous form as the monohydrochloride salt (etaserti HCl).

[0083] In a particular embodiment of the invention, the pharmaceutical composition comprises 50 mg to 1000 mg of the Akt inhibitor.

[0084] In a particular embodiment of the invention, the pharmaceutical composition comprises 100 mg to 800 mg of the Akt inhibitor.

[0085] In a particular embodiment of the invention, the pharmaceutical composition comprises 100 mg to 300 mg of the Akt inhibitor.

[0086] In a specific embodiment of the invention, the pharmaceutical composition comprises 100 mg, 200 mg or 300 mg of the Akt inhibitor.

[0087] Filler (inside particles)

[0088] As mentioned above, amorphous etaserti monohydrochloride is a highly brittle API, making processing using direct compression very difficult. It has been found that microcrystalline cellulose with high plastic deformation properties as a filler advantageously compensates for the brittleness of etaserti. It has further been found that a combination of microcrystalline cellulose and pregelatinized starch as a filler together with etaserti provides a composition with improved granulation properties due to the water absorption properties of the pregelatinized starch and also due to improved compression properties compared to a composition of microcrystalline cellulose and API alone.

[0089] It has further been found that alternative fillers, for example, mannitol and lactose reduce tablet hardness.

[0090] It has further been found that alternative combinations of fillers, such as for example microcrystalline cellulose in combination with lactose, increase the risk of tablet splitting.

[0091] In a particular embodiment of the invention, the pharmaceutical composition comprises one or more fillers selected from the group consisting of microcrystalline cellulose, pregelatinized starch, corn starch, lactose, mannitol, calcium phosphate, hydroxypropyl cellulose, polyethylene glycol, sorbitol, maltodextrin and dextrose.

[0092] In a particular embodiment of the invention, the pharmaceutical composition comprises one or two fillers selected from microcrystalline cellulose and pregelatinized starch.

[0093] In a particular embodiment of the invention, the pharmaceutical composition comprises microcrystalline cellulose and pregelatinized starch as fillers.

[0094] In a particular embodiment of the invention, the pharmaceutical composition comprises 20% wt-75% wt of one or more fillers, more particularly 30% wt-70% wt, even more particularly 40% wt-65% wt, most particularly 50% wt-60% wt.

[0095] In a particular embodiment of the invention, the pharmaceutical composition comprises 20%wt-75%wt of one or more intragranular fillers, more particularly 30%wt-70%wt, even more particularly 40%wt-65%wt, most particularly 50%wt-60%wt.

[0096] In a particular embodiment of the invention, the pharmaceutical composition comprises 20% wt-65% wt of microcrystalline cellulose as filler, more particularly 30% wt-55% wt, even more particularly 40% wt-50% wt, most particularly 40% wt-45% wt.

[0097] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-50% wt of pregelatinized starch as filler, more particularly 0-30% wt, even more particularly 5% wt-15% wt, most particularly 10% wt-15% wt.

[0098] In a specific embodiment of the present invention, the pharmaceutical composition comprises 20% wt-65% wt of microcrystalline cellulose and 0-50% wt of pregelatinized starch as filler, more particularly 30% wt-55% wt of microcrystalline cellulose and 0-30% wt of pregelatinized starch as filler, even more particularly 40% wt-50% wt of microcrystalline cellulose and 5% wt-15% wt of pregelatinized starch as filler, most particularly 40% wt-45% wt of microcrystalline cellulose and 10% wt-15% wt of pregelatinized starch as filler.

[0099] Binder (in granule)

[0100] Surprisingly, it has been found that the particle properties of the granules can be significantly improved by adding one or more binders to the intragranular matrix. Povidone K90 (polyvinylpyrrolidone K90, average Mw of 360,000) improves binding capacity, increases particle size distribution (PSD) of the granules and improves particle shape (reduced amount of fine particles) without affecting dissolution performance and hardness. It has been found that granules comprising povidone K90 exhibit improved properties such as improved binding capacity (significantly better binding of API), reduced granule friability, increased granule PSD and reduced amount of fine particles compared to povidone K30, while maintaining similar dissolution and disintegration performance at comparable hardness.

[0101] In one embodiment of the invention, the pharmaceutical composition comprises one or more binders selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl acetate, polyvinyl alcohol, gelatin and gum arabic.

[0102] In one embodiment of the present invention, the pharmaceutical composition comprises one or more binders selected from the group consisting of povidone K90, povidone K30, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, polyvinyl acetate, polyvinyl alcohol, gelatin and gum arabic.

[0103] In a particular embodiment of the invention, the binder is polyvinylpyrrolidone.

[0104] In a particular embodiment of the invention, the binder is povidone K90.

[0105] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-10% wt of a binder, more particularly 0-5% wt, even more particularly 1.5% wt-3.5% wt.

[0106] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-10% wt of intragranular binder, more particularly 0-5% wt, even more particularly 1.5% wt-3.5% wt.

[0107] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-10% wt of Povidone K90 as a binder, more particularly 0-5% wt, even more particularly 1.5% wt-3.5% wt.

[0108] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-10% wt of intragranular povidone K90 as binder, more particularly 0-5% wt, even more particularly 1.5% wt-3.5% wt.

[0109] Disintegrants (intragranular and / or extragranular)

[0110] The inventors of the present invention surprisingly found that the disintegration properties and drug release profile can be improved by the additional use of a disintegrant. Croscarmellose sodium has been found to be a particularly beneficial (super) disintegrant which does not introduce any peroxide into the pharmaceutical composition.

[0111] In one embodiment of the invention, the pharmaceutical composition comprises one or more disintegrants selected from the group consisting of croscarmellose sodium (internal cross-linked sodium carboxymethylcellulose, E468), crospovidone (polyvinylpyrrolidone, PVPP, E1202, a highly cross-linked modification of polyvinylpyrrolidone (PVP), sodium starch glycolate, sodium alginate, starch, pectin, cellulose derivatives and croscarmellose calcium.

[0112] In one embodiment of the invention, the pharmaceutical composition comprises croscarmellose sodium as a disintegrant.

[0113] In a particular embodiment of the invention, the pharmaceutical composition comprises 3% wt-10% wt of disintegrant, more particularly 4% wt-8% wt, even more particularly 5% wt-7% wt.

[0114] In a particular embodiment of the invention, the pharmaceutical composition comprises 3% wt-10% wt of intragranular disintegrant, more particularly 4% wt-8% wt, even more particularly 5% wt-7% wt.

[0115] In a particular embodiment of the invention, the pharmaceutical composition comprises 3% wt-10% wt of extragranular disintegrant, more particularly 4% wt-8% wt, even more particularly 5% wt-7% wt.

[0116] In a particular embodiment of the invention, the pharmaceutical composition comprises 3% wt-10% wt of croscarmellose sodium as disintegrant, more particularly 4% wt-8% wt, even more particularly 5% wt-7% wt.

[0117] In a particular embodiment of the invention, the pharmaceutical composition comprises 3% wt-10% wt of intragranular croscarmellose sodium as disintegrant, more particularly 4% wt-8% wt, even more particularly 5% wt-7% wt.

[0118] In a particular embodiment of the invention, the pharmaceutical composition comprises 3% wt-10% wt of extragranular croscarmellose sodium as disintegrant, more particularly 4% wt-8% wt, even more particularly 5% wt-7% wt.

[0119] In a particular embodiment of the invention, the disintegrant is extragranular.

[0120] Lubricant (extragranular)

[0121] The inventors of the present invention have found that effective lubrication can be achieved by additional use of a lubricant to support robust tablet compression. Stearic acid or magnesium stearate have been found to be particularly beneficial lubricants suitable for obtaining acceptable lubrication during tablet compression and simultaneously providing a target drug release profile.

[0122] In one embodiment of the present invention, the pharmaceutical composition further comprises one or more lubricants.

[0123] In one embodiment of the present invention, the pharmaceutical composition further comprises one or more lubricants selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, talc, calcium stearate and stearyl alcohol.

[0124] In one embodiment of the present invention, the pharmaceutical composition further comprises magnesium stearate as a lubricant.

[0125] In one embodiment of the present invention, the pharmaceutical composition further comprises stearic acid as a lubricant.

[0126] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-5% wt of glidant, more particularly 0-3% wt, even more particularly 0.5% wt-1.5% wt.

[0127] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-5% wt of extragranular glidant, more particularly 0-3% wt, even more particularly 0.5% wt-1.5% wt.

[0128] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-5% wt of magnesium stearate as glidant, more particularly 0-3% wt, even more particularly 0.5% wt-1.5% wt.

[0129] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-5% wt of extragranular magnesium stearate as glidant, more particularly 0-3% wt, even more particularly 0.5% wt-1.5% wt.

[0130] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-5% wt of extragranular stearic acid as glidant, more particularly 0-3% wt, even more particularly 0.5% wt-1.5% wt.

[0131] Hygroscopic agent (in granules)

[0132] As mentioned above, amorphous etanercept monohydrochloride exhibits very high solubility and very high hygroscopicity, which poses severe challenges to processing as well as stability and shelf life of the final product.

[0133] The inventors of the present invention surprisingly found that a pharmaceutical composition comprising amorphous ectaserti hydrochloride and a hygroscopic agent (intragranular) can prevent the dissolution of amorphous ectaserti hydrochloride during granulation. Therefore, the pharmaceutical composition comprising amorphous ectaserti hydrochloride and a hygroscopic agent significantly improves processability by reducing the risk of over-wetting and over-granulation and by improving process robustness.

[0134] In a particular embodiment of the invention, the pharmaceutical composition comprises one or more hygroscopic agents.

[0135] In a particular embodiment of the present invention, the pharmaceutical composition comprises one or more hygroscopic agents selected from colloidal silicon dioxide, fumed silicon dioxide, non-fumed silicon dioxide, Pregelatinized starch, corn starch and cross-linked carboxymethyl cellulose.

[0136] In a particular embodiment of the present invention, the hygroscopic agent is colloidal silicon dioxide.

[0137] In a particular embodiment of the present invention, the hygroscopic agent is colloidal fumed silica.

[0138] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-10% wt of hygroscopic agent, more particularly 0-5% wt, even more particularly 2% wt-4% wt.

[0139] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-10% wt of intragranular hygroscopic agent, more particularly 0-5% wt, even more particularly 2% wt-4% wt.

[0140] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-10% wt of colloidal silicon dioxide as hygroscopic agent, more particularly 0-5% wt, even more particularly 2% wt-4% wt.

[0141] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-10% wt of intragranular colloidal silicon dioxide as hygroscopic agent, more particularly 0-5% wt, even more particularly 2% wt-4% wt.

[0142] Glidant (extragranular)

[0143] By additional use of an extragranular glidant, glidant properties (e.g., blend flowability) can be improved and tablet splitting can be reduced. Colloidal silicon dioxide has been found to be a particularly beneficial glidant to achieve suitable final blend flowability and reduce the risk of splitting. Glidants have been found to improve granule flow to support a robust tablet compression process and target content uniformity.

[0144] Magnesium stearate has been found to be a particularly beneficial glidant to achieve suitable lubrication during tablet compression and drug release profile. The use of colloidal silicon dioxide in the presence of magnesium stearate is particularly effective in reducing the risk of tablet splitting.

[0145] In one embodiment of the invention, the pharmaceutical composition comprises one or more glidants.

[0146] In one embodiment of the present invention, the pharmaceutical composition comprises one or more glidants selected from the group consisting of colloidal silicon dioxide, talc, magnesium stearate, polyethylene glycol, calcium stearate and cetyl alcohol.

[0147] In one embodiment of the invention, the pharmaceutical composition comprises colloidal silicon dioxide as a glidant.

[0148] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-5% wt of glidant, more particularly 0-3% wt, even more particularly 0.5% wt-1.5% wt.

[0149] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-5% wt of extragranular glidant, more particularly 0-3% wt, even more particularly 0.5% wt-1.5% wt.

[0150] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-5% wt of colloidal silicon dioxide as glidant, more particularly 0-3% wt, even more particularly 0.5% wt-1.5% wt.

[0151] In a particular embodiment of the invention, the pharmaceutical composition comprises 0-5% wt of extragranular colloidal silicon dioxide as glidant, more particularly 0-3% wt, even more particularly 0.5% wt-1.5% wt.

[0152] In a particular embodiment of the present invention, the pharmaceutically acceptable intragranular excipients comprise one or more of a filler, a hygroscopic agent and a binder.

[0153] In a particular embodiment of the invention, the pharmaceutically acceptable extragranular excipients comprise one or more of a disintegrant, a lubricant and a glidant.

[0154] In a particular embodiment of the invention, the pharmaceutically acceptable intragranular excipients comprise one or more of a filler, a hygroscopic agent and a binder and the pharmaceutically acceptable extragranular excipients comprise one or more of a disintegrant, a lubricant and a glidant.

[0155] In a specific embodiment of the present invention, the pharmaceutically acceptable intragranular excipients include microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide and povidone K90.

[0156] In a particular embodiment of the invention, the pharmaceutically acceptable extragranular excipients include croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0157] In one embodiment of the invention, the pharmaceutically acceptable intragranular excipients include microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide and povidone K90 and the pharmaceutically acceptable extragranular excipients include croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

[0158] Film coating

[0159] Stability, appearance, swallowability and taste masking can be improved by the additional use of a non-functional film coating. Especially low titanium dioxide Opadry (a PVA (polyvinyl alcohol) based film coating system) is a particularly beneficial film coating suitable for achieving uniformity in coating color and coating thickness.

[0160] In one embodiment of the present invention, the pharmaceutical composition further comprises a film coating selected from a PVA-based film coating or a HPMC-based film coating.

[0161] In one embodiment of the present invention, the pharmaceutical composition further comprises a film coating selected from PVA based film coating or HPMC based film coating.

[0162] In one embodiment of the present invention, the pharmaceutical composition further comprises Opadry PVA-based film coatings, especially low titanium dioxide grades of Opadry PVA based film coating.

[0163] In a particular embodiment of the present invention, the pharmaceutical composition comprises 0-7%wt of Opadry PVA based film coating, more particularly 1% wt-6% wt, even more particularly 3% wt-5% wt.

[0164] Pharmaceutical composition

[0165] It has been found that oral immediate release film-coated tablets are particularly suitable dosage forms comprising amorphous etanercept monohydrochloride because of safety, efficacy and good patient compliance, for example, easy swallowing, and no taste or odor.

[0166] The pharmaceutical composition of the present invention exhibits good stability for more than 24 months without complicated storage requirements.

[0167] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor and one or more pharmaceutically acceptable excipients selected from fillers, binders and disintegrants.

[0168] One embodiment relates to a pharmaceutical composition comprising (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etasertib) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients selected from fillers, binders and disintegrants.

[0169] One embodiment relates to a pharmaceutical composition as described herein, comprising (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etasertib) or a pharmaceutically acceptable salt thereof, one or more fillers, a binder, and a disintegrant.

[0170] One embodiment relates to a pharmaceutical composition as described herein, wherein the intragranular matrix comprises (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etasertide) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients selected from fillers, binders and disintegrants.

[0171] One embodiment relates to a pharmaceutical composition as described herein, comprising 50 mg to 1000 mg of (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etasertib) or a pharmaceutically acceptable salt thereof.

[0172] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor and one or more fillers.

[0173] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor and a binding agent.

[0174] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor, one or more fillers, and a binder.

[0175] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor, one or more fillers, a binder, and a disintegrant.

[0176] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor, one or more fillers, a binder, a disintegrant, and a lubricant.

[0177] One embodiment relates to a pharmaceutical composition, wherein the intragranular matrix comprises an Akt inhibitor and one or more pharmaceutically acceptable excipients selected from fillers, binders and disintegrants.

[0178] One embodiment relates to a pharmaceutical composition wherein the intraparticle matrix comprises an Akt inhibitor and one or more fillers.

[0179] One embodiment relates to a pharmaceutical composition, wherein the intraparticle matrix comprises an Akt inhibitor and a binder.

[0180] One embodiment relates to a pharmaceutical composition wherein the intraparticle matrix comprises an Akt inhibitor, one or more fillers, and a binder.

[0181] One embodiment relates to a pharmaceutical composition wherein the intragranular matrix comprises an Akt inhibitor, one or more fillers, a binder, and a disintegrant.

[0182] One embodiment relates to a pharmaceutical composition wherein the extragranular matrix comprises a disintegrant.

[0183] In a particular embodiment of the present invention, the pharmaceutical composition further comprises a lubricant.

[0184] In a particular embodiment of the present invention, the pharmaceutical composition further comprises an extragranular lubricant.

[0185] In a particular embodiment of the present invention, the pharmaceutical composition further comprises a hygroscopic agent.

[0186] In a particular embodiment of the present invention, the pharmaceutical composition further comprises an intragranular hygroscopic agent.

[0187] In a particular embodiment of the present invention, the pharmaceutical composition further comprises a glidant.

[0188] In a particular embodiment of the present invention, the pharmaceutical composition further comprises an extragranular glidant.

[0189] In a particular embodiment of the present invention, the pharmaceutical composition further comprises a film coating.

[0190] In a particular embodiment of the present invention, the pharmaceutical composition is suitable for oral administration.

[0191] In a particular embodiment of the invention, the pharmaceutical composition is a solid.

[0192] In a particular embodiment of the present invention, the pharmaceutical composition is a tablet, capsule or sachet, wherein the tablet, capsule or sachet comprises granules comprising the Akt inhibitor and one or more pharmaceutically acceptable excipients selected from fillers, binders and disintegrants.

[0193] In a particular embodiment of the present invention, the pharmaceutical composition is a tablet, a capsule or a sachet, wherein the tablet, the capsule or the sachet comprises granules comprising an Akt inhibitor and one or more fillers.

[0194] In a particular embodiment of the present invention, the pharmaceutical composition is a tablet, a capsule or a sachet, wherein the tablet, the capsule or the sachet comprises granules comprising an Akt inhibitor and a binder.

[0195] In a particular embodiment of the present invention, the pharmaceutical composition is a tablet, a capsule or a sachet, wherein the tablet, the capsule or the sachet comprises granules comprising an Akt inhibitor, one or more fillers and a binder.

[0196] In a particular embodiment of the present invention, the pharmaceutical composition is a tablet, a capsule or a sachet, wherein the tablet, the capsule or the sachet comprises granules comprising an Akt inhibitor, one or more fillers, a binder and a disintegrant.

[0197] In a particular embodiment of the invention, the pharmaceutical composition is a tablet.

[0198] In a particular embodiment of the present invention, the pharmaceutical composition is an immediate release film-coated tablet.

[0199] In a particular embodiment of the invention, the pharmaceutical composition comprises:

[0200] ● 20%wt-40%wt of etanercept or a pharmaceutically acceptable salt thereof,

[0201] ●20%wt-65%wt microcrystalline cellulose as filler,

[0202] ●0-50%wt of pregelatinized starch as filler,

[0203] ●0-10%wt colloidal silicon dioxide as a hygroscopic agent,

[0204] ●1%wt-10%wt of polyvinyl pyrrolidone as a binder,

[0205] ●0-5%wt colloidal silicon dioxide as a glidant,

[0206] ●3%wt-10%wt of cross-linked carboxymethyl cellulose sodium as a disintegrant,

[0207] • 0-5%wt of magnesium stearate as lubricant.

[0208] In a particular embodiment of the invention, the pharmaceutical composition comprises:

[0209] ● 20%wt-40%wt of etanercept or a pharmaceutically acceptable salt thereof,

[0210] ●20%wt-65%wt microcrystalline cellulose as filler,

[0211] ●0-50%wt pregelatinized starch as filler,

[0212] ●0-10%wt colloidal silicon dioxide as a hygroscopic agent,

[0213] ●1%wt-10%wt of polyvinyl pyrrolidone as a binder,

[0214] ●0-5%wt colloidal silicon dioxide as a glidant,

[0215] ●3%wt-10%wt of cross-linked carboxymethyl cellulose sodium as a disintegrant,

[0216] 0-5%wt magnesium stearate as lubricant,

[0217] The net mass of etanercept free base is 50 mg to 800 mg.

[0218] In a particular embodiment of the invention, the pharmaceutical composition comprises:

[0219] ● 20%wt-40%wt of etaserti free base or etaserti monohydrochloride,

[0220] ●40%wt-45%wt of microcrystalline cellulose as filler,

[0221] ●10%wt-15%wt pregelatinized starch as filler,

[0222] ●2%wt-4%wt colloidal silicon dioxide as a hygroscopic agent,

[0223] ●1.5%wt-3.5%wt of polyvinyl pyrrolidone as a binder,

[0224] ●0.5%wt-1.5%wt colloidal silicon dioxide as a glidant,

[0225] ●5%wt-7%wt of cross-linked carboxymethylcellulose sodium as a disintegrant,

[0226] - 0.5%wt - 1.5%wt of magnesium stearate as a lubricant.

[0227] In a particular embodiment of the invention, the pharmaceutical composition comprises:

[0228] ● 20%wt-40%wt of etaserti free base or etaserti monohydrochloride,

[0229] ●40%wt-45%wt of microcrystalline cellulose as filler,

[0230] ●10%wt-15%wt pregelatinized starch as filler,

[0231] ●2%wt-4%wt colloidal silicon dioxide as a hygroscopic agent,

[0232] ●1.5%wt-3.5%wt of polyvinyl pyrrolidone as a binder,

[0233] ●0.5%wt-1.5%wt colloidal silicon dioxide as a glidant,

[0234] ●5%wt-7%wt of cross-linked carboxymethylcellulose sodium as a disintegrant,

[0235] 0.5%wt-1.5%wt of magnesium stearate as a lubricant,

[0236] The net mass of etanercept free base is 50 mg to 300 mg.

[0237] In a particular embodiment of the invention, the pharmaceutical composition comprises:

[0238] 95-105 mg of etanercept free base or the corresponding amount of etanercept monohydrochloride,

[0239] 150-155 mg of microcrystalline cellulose as filler,

[0240] ●40-45 mg of pregelatinized starch as filler,

[0241] ●8-12 mg of colloidal silicon dioxide as a hygroscopic agent,

[0242] ●7-10 mg of polyvinyl pyrrolidone as a binder,

[0243] ●2-5 mg of colloidal silicon dioxide as a glidant,

[0244] ●20-22 mg of cross-linked carboxymethyl cellulose sodium as a disintegrant,

[0245] ●2-5 mg of magnesium stearate as a lubricant.

[0246] In a particular embodiment of the invention, the pharmaceutical composition comprises:

[0247] 99-101 mg of etanercept free base or the corresponding amount of etanercept monohydrochloride,

[0248] ●151.5-153.5 mg of microcrystalline cellulose as filler,

[0249] ●41-43 mg of pregelatinized starch as filler,

[0250] ●9.5-11.5 mg of colloidal silicon dioxide as a hygroscopic agent,

[0251] ●7.75-9.75 mg of polyvinyl pyrrolidone as a binder,

[0252] ●2.5-4.5 mg of colloidal silicon dioxide as a glidant,

[0253] ●20-22 mg of cross-linked carboxymethyl cellulose sodium as a disintegrant,

[0254] ●2.5-4.5 mg of magnesium stearate as a lubricant.

[0255] In a particular embodiment of the invention, the pharmaceutical composition comprises:

[0256] 195-205 mg of etanercept free base or the corresponding amount of etanercept monohydrochloride,

[0257] ●300-310 mg of microcrystalline cellulose as filler,

[0258] ●80-90 mg of pregelatinized starch as filler,

[0259] ●19-23 mg of colloidal silicon dioxide as a hygroscopic agent,

[0260] ●15-20 mg of polyvinyl pyrrolidone as a binder,

[0261] 5-10 mg of colloidal silicon dioxide as a glidant,

[0262] ●40-44 mg of cross-linked carboxymethyl cellulose sodium as a disintegrant,

[0263] ●5-10 mg of magnesium stearate as a lubricant.

[0264] In a particular embodiment of the invention, the pharmaceutical composition comprises:

[0265] 199-201 mg of etanercept free base or the corresponding amount of etanercept monohydrochloride,

[0266] ●304.5-306.5mg of microcrystalline cellulose as filler,

[0267] ●83-85 mg of pregelatinized starch as filler,

[0268] ●20-22 mg of colloidal silicon dioxide as a hygroscopic agent,

[0269] ●16.5-18.5 mg of polyvinyl pyrrolidone as a binder,

[0270] ●6-8 mg of colloidal silicon dioxide as a glidant,

[0271] ●41-43 mg of cross-linked carboxymethyl cellulose sodium as a disintegrant,

[0272] ●6-8 mg of magnesium stearate as a lubricant.

[0273] Method for producing pharmaceutical composition

[0274] The present invention further provides a method for producing a pharmaceutical composition as described herein. Figure 1 A method for producing a pharmaceutical composition.

[0275] One embodiment of the present invention relates to a method for producing particles suitable for further use in the pharmaceutical compositions described herein, the method comprising the following steps:

[0276] a) optionally sieving the one or more fillers, optionally sieving the disintegrant and, where present, the hygroscopic agent by passing through a grinder;

[0277] b) preparing a premix by premixing the one or more fillers and, where present, the hygroscopic agent together with the API, and then introducing the premix into a fluid bed granulator;

[0278] c) preparing a granulation solution by dissolving the binder in a solvent and then stirring until a clear solution is obtained; alternatively, the binder may be added during the premix preparation of step b), in which case the granulation solution comprises a solvent;

[0279] d) spraying the granulation solution onto the fluidized premix in the fluidized bed granulator to obtain wet granules;

[0280] e) optionally drying the wet granules obtained in the fluid bed granulator.

[0281] One embodiment of the present invention relates to a method for preparing a pharmaceutical composition as described herein, comprising the following steps:

[0282] a) optionally sieving the one or more fillers and, where present, the hygroscopic agent by passing through a grinder;

[0283] b) preparing a premix by premixing the one or more fillers and, where present, the hygroscopic agent together with the API, and then introducing the premix into a fluid bed granulator;

[0284] c) preparing a granulation solution by dissolving the binder in a solvent and then stirring until a clear solution is obtained; alternatively, the binder may be added during the premix preparation of step b), in which case the granulation solution comprises a solvent;

[0285] d) spraying the granulation solution onto the fluidized premix in the fluidized bed granulator to obtain wet granules;

[0286] e) optionally drying the resulting wet granules in the fluidized bed granulator;

[0287] f) optionally sieving the resulting granules by passing through a grinder;

[0288] g) optionally sieving the disintegrant and, if present, the glidant by passing through a mill;

[0289] h) preparing a first mixture by mixing the disintegrant and, if present, the glidant together with the dry granules in a mixer; alternatively or additionally, the disintegrant may be added during the premix preparation of step b);

[0290] i) optionally sieving the lubricant by passing it through a grinder;

[0291] j) preparing a second mixture by mixing the lubricant with the first mixture in a mixer;

[0292] k) compressing the second mixture into tablets using a tablet press and punches;

[0293] l) Optionally coat the tablets in a pan coater.

[0294] In a particular embodiment of the present invention, the grinder in step a) has a mesh size of 1.0 mm to 2.0 mm, more particularly a mesh size of 1.5 mm.

[0295] In a particular embodiment of the present invention, the material sieved in step a) further comprises a binder.

[0296] In a particular embodiment of the present invention, the material sieved in step a) further comprises a disintegrant.

[0297] In a particular embodiment of the present invention, the material sieved in step a) further comprises a binder and a disintegrant.

[0298] In a particular embodiment of the present invention, the premix in step b) further comprises a binder.

[0299] In a particular embodiment of the present invention, the premix in step b) further comprises a disintegrant.

[0300] In a particular embodiment of the present invention, the premix in step b) further comprises a binder and a disintegrant.

[0301] In a particular embodiment of the present invention, the fluidized bed granulator in step b) is a top spray granulator or a bottom spray granulator.

[0302] In a particular embodiment of the present invention, the fluidized bed granulator in step b) is a top spray granulator.

[0303] In a particular embodiment of the present invention, the fluidized bed granulator in step b) is a bottom spray granulator.

[0304] In a particular embodiment of the present invention, the premix in b) is further mixed in a preheating stage at elevated temperature, in particular at 30 to 80°C or 40 to 80°C.

[0305] In a particular embodiment of the present invention, the premix in b) is further mixed in a preheating phase at elevated temperature, wherein the preheating phase lasts less than 15 minutes, or less than 10 minutes, or less than 5 minutes.

[0306] In a particular embodiment of the present invention, the granulation solution in step c) is prepared with a solvent comprising water.

[0307] In a particular embodiment of the present invention, the granulation solution in step c) is prepared with water as solvent.

[0308] In a particular embodiment of the present invention, the granulation solution in step c) is prepared at a temperature of 5 to 60°C, in particular 20 to 30°C, most in particular 25°C.

[0309] In a particular embodiment of the present invention, the spraying in step d) is carried out at a spraying pressure of the granulating solution of 0.1 to 5 bar, or 2 to 4 bar, in particular 1 to 3 bar.

[0310] In a particular embodiment of the present invention, the spraying in step d) is carried out at a spraying rate of the granulating solution of 50 to 250 g / min, or 50 to 200 g / min, in particular 75 to 125 g / min.

[0311] In a particular embodiment of the present invention, the spraying in step d) is performed using a nozzle having a diameter of 0.8 to 2 mm, or 1.0 to 1.6 mm, in particular a diameter of 1.0 to 1.4 mm.

[0312] In a particular embodiment of the present invention, the drying in step e) is carried out with air, in particular with air at an air temperature of 50°C to 80°C, most in particular 65°C.

[0313] In a particular embodiment of the present invention, the drying in step e) is carried out at an air flow rate of 300-600 m / s. 3 / h or 360-560m 3 / h with air.

[0314] In a particular embodiment of the present invention, the drying in step e) is carried out for less than 1 hour.

[0315] In a particular embodiment of the present invention, the grinder in step f) has a mesh size of 1.0 mm to 2.0 mm, more particularly a mesh size of 1.5 mm.

[0316] In a particular embodiment of the present invention, the grinder in step g) has a mesh size of 1.0 mm to 2.0 mm, more particularly a mesh size of 1.5 mm.

[0317] In a particular embodiment of the present invention, the grinder in step i) has a mesh size of 1.0 mm to 2.0 mm, more particularly a mesh size of 1.5 mm.

[0318] In a particular embodiment of the present invention, the compression in step k) is carried out at a main compression force of 6 to 20 kN, in particular 8 to 15 kN or 10 to 14 kN.

[0319] In a particular embodiment of the invention, wherein the pharmaceutical composition comprises 95-105 mg of etaserti free base (or the corresponding amount of etaserti monohydrochloride), the compression in step k) takes place at a main compression force of 6 to 14 kN, in particular 8-10 kN.

[0320] In a particular embodiment of the invention, wherein the pharmaceutical composition comprises 195-205 mg of etaserti free base (or the corresponding amount of etaserti monohydrochloride), the compression in step k) takes place at a main compression force of 9 to 20 kN, in particular 13 to 15 kN.

[0321] In a particular embodiment of the invention, the coating in step 1) is carried out in a pan coater, wherein the aqueous coating suspension is sprayed onto the tablets.

[0322] In a specific embodiment of the present invention, the coating in step 1) is carried out in a pan coater, wherein the aqueous coating suspension is sprayed onto the tablets using a nozzle having a diameter of 0.5 to 1.5 mm, or a diameter of 0.8 to 1.5 mm, in particular a diameter of 0.8 to 1.2 mm.

[0323] In a particular embodiment of the invention, the coating in step 1) is carried out in a pan coater, wherein the aqueous coating suspension is sprayed onto the tablets at a spray pressure of 1.5 to 3 bar, in particular 2 to 2.5 bar.

[0324] In a particular embodiment of the invention, the coating in step 1) is followed by the use of air at an inlet temperature of 50° C. to 75° C., in particular 60° C. and an inlet flow rate of 400 to 800 m / s. 3 / h, especially 450m 3 / h for drying.

[0325] Spray drying method

[0326] The present invention also provides a spray drying method without the use of problematic solvents for producing homogeneous and stable amorphous etanercept monohydrochloride particles having improved particle size, particle shape and particle properties, such as improved flowability and bulk density, which can be further used in the production of pharmaceutical compositions without the need for additional treatment, conditioning or reprocessing.

[0327] Ataxerti solvate was successfully obtained using a solvent selected from the following list:

[0328]

[0329]

[0330] The ideal solvate is based on a solvent that is classified as a USP Class 3 solvent (based on risk assessment or its potential toxicity level), is miscible with water, has a high vapor pressure and high volatility and should not form genotoxic byproducts.

[0331] A specific solvate of eptasherti suitable as a starting material for the production of eptasherti monohydrochloride (eptasherti·HCl) is an eptasherti solvate comprising a solvent selected from the following list in the crystal lattice: methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl propionate, methyl ethyl ketone, 2-pentanone, methyl butyl ketone, methyl isobutyl ketone, diisopropyl ketone, diisobutyl ketone and methyl tert-butyl ether.

[0332] The most specific solvate of eptasherti suitable as a starting material for the production of eptasherti monohydrochloride (eptasherti·HCl) is an eptasherti solvate comprising a solvent selected from the following list in the crystal lattice: ethyl acetate, n-propyl acetate, n-butyl acetate and methyl ethyl ketone.

[0333] A particularly preferred solvate of etaserti suitable as a starting material for the production of etaserti monohydrochloride (etaserti·HCl) is ethyl etaserti acetate, also known as etaserti ethyl acetate, characterized in that a single crystal X-ray diffraction pattern comprises peaks at 2θ diffraction angles of 6.6°, 13.9°, 16.6°, 17.4°, 18.2°, 19.0°, 20.5°, 21.4°, 22.4° and 22.6° (±0.2°).

[0334] A particularly preferred solvate of etaserti suitable as a starting material for the production of etaserti monohydrochloride (etaserti·HCl) is ethyl etaserti acetate, also known as etaserti ethyl acetate, characterized in that the XRPD diffraction pattern comprises XRPD peaks at 2θ diffraction angles of 6.6°, 8.4°, 10.5°, 13.6°, 16.4°, 17.2°, 18.8°, 20.0°, 21.1° and 22.1° (±0.2°).

[0335] A particularly preferred solvate of etaserti suitable as a starting material for the production of etaserti monohydrochloride (etaserti·HCl) is etaserti n-propyl acetate, also known as etaserti n-propyl acetate. A specific solid form of etaserti n-propyl acetate is characterized by an XRPD diffraction pattern comprising peaks at 2θ diffraction angles of 6.2°, 6.9°, 9.5°, 14.4°, 16.9°, 17.4°, 18.0°, 19.8°, 20.7°, and 22.1° (±0.2°).

[0336] Another specific solid form of etasertin acetate n-propyl is characterized by an XRPD diffraction pattern comprising peaks at 2θ diffraction angles of 6.5°, 7.5°, 9.9°, 12.2°, 14.5°, 16.6°, 17.0°, 19.6°, 20.6°, and 24.5° (±0.2°).

[0337] Another specific solid form of etasertin acetate n-propyl is characterized by an XRPD diffraction pattern comprising peaks at 2θ diffraction angles of 5.8°, 6.9°, 12.3°, 14.1°, 17.4°, 18.1°, 18.7°, 19.3°, 20.4°, and 20.6° (±0.2°).

[0338] A particularly preferred solvate of etaserti suitable as a starting material for the production of etaserti monohydrochloride (etaserti·HCl) is etaserti n-butyl acetate, also known as etaserti n-butyl acetate, characterized in that the XRPD diffraction pattern comprises peaks at 2θ diffraction angles of 5.8°, 7.5°, 12.0°, 13.7°, 14.8°, 16.9°, 18.8°, 19.1°, 21.8° and 22.7° (±0.2°).

[0339] A particularly preferred solvate of etaserti suitable as a starting material for the production of etaserti monohydrochloride (etaserti·HCl) is etaserti methyl ethyl ketone, also known as etaserti 2-butanone, characterized in that the XRPD diffraction pattern comprises XRPD peaks at 2θ diffraction angles of 5.8°, 7.6°, 12.0°, 13.8°, 14.7°, 16.3°, 17.1°, 18.8°, 19.1° and 22.8° (±0.2°).

[0340] A particularly preferred solvate of etaserti suitable as a starting material for producing etaserti monohydrochloride (etaserti·HCl) is ethyl etasertiate.

[0341] A particularly preferred solvate of ectaserti suitable as a starting material for producing ectaserti monohydrochloride (ectaserti·HCl) is ectaserti monohydrochloride ethyl acetate solvate (ectaserti·HCl·EtOAc) containing less than 10% wt of ethyl acetate.

[0342] A particularly preferred solvate of ectaserti suitable as a starting material for producing ectaserti monohydrochloride (ectaserti·HCl) is ectaserti monohydrochloride ethyl acetate solvate (ectaserti·HCl·EtOAc) containing less than 8% wt of ethyl acetate.

[0343] A particularly preferred solvate of ectaserti suitable as a starting material for producing ectaserti monohydrochloride (ectaserti·HCl) is ectaserti monohydrochloride ethyl acetate solvate (ectaserti·HCl·EtOAc) containing less than 7% wt of ethyl acetate.

[0344] One embodiment of the present invention relates to a method for preparing amorphous etanercept monohydrochloride, the method comprising the following steps:

[0345] a) dissolving a solvate of etanercept in a solvent;

[0346] b) feeding the resulting feed solution into a spray dryer unit;

[0347] c) atomizing the solution in a drying chamber to produce a mist;

[0348] d) mixing the generated mist with a drying gas, thereby evaporating the solvent;

[0349] e) separating the obtained amorphous etanercept monohydrochloride powder from the drying gas; and

[0350] f) collecting the obtained amorphous etanercept monohydrochloride powder.

[0351] One embodiment of the present invention relates to a method for preparing amorphous etanercept monohydrochloride, the method comprising the following steps:

[0352] g) dissolving etaserti monohydrochloride ethyl acetate solvate (etaserti·HCl·EtOAc) in a solvent;

[0353] h) feeding the resulting feed solution into a spray dryer unit;

[0354] i) atomizing the solution in a drying chamber to generate a mist;

[0355] j) mixing the generated mist with a drying gas, thereby evaporating the solvent;

[0356] k) separating the obtained amorphous etanercept monohydrochloride powder from the drying gas; and

[0357] l) collecting the obtained amorphous etanercept monohydrochloride powder.

[0358] Optionally, the substantially powder-free drying gas containing evaporated solvent may be recycled as follows:

[0359] m) introducing the dry gas from the cyclone into the filter bag housing, where very fine particles are retained in the bag filters;

[0360] n) cooling the drying gas in a condenser to produce solvent condensation;

[0361] o) The re-dried drying gas is reheated and recycled into the drying chamber.

[0362] Specifically, the method involves preparing amorphous ectaserti monohydrochloride (ectaserti·HCl) from ectaserti monohydrochloride ethyl acetate solvate (ectaserti·HCl·EtOAc) using a spray dryer with a rotary wheel atomizer.

[0363] Specifically, the method involves preparing amorphous eptashertib monohydrochloride (eptashertib·HCl) from eptashertib solvate using a spray dryer with a rotating wheel atomizer.

[0364] In a particular embodiment, the dissolution of step a) is carried out at a temperature ranging from 5°C to 50°C, more particularly at a temperature ranging from 20°C to 25°C.

[0365] In a particular embodiment, the solvent of step a) comprises water, in particular water, most in particular purified water.

[0366] In a particular embodiment, the feed solution obtained in step a) is an aqueous solution.

[0367] In a specific embodiment, the feed solution obtained in step a) comprises 5% to 35% (w / w) etaserti·HCl·EtOAc, or more particularly 10% to 30% (w / w) etaserti·HCl·EtOAc, and most particularly 18%-22% (w / w) etaserti·HCl·EtOAc.

[0368] In a specific embodiment, the feed solution in step b) is fed at a feed rate of 7 to 20 kg / h, in particular 10 to 12 kg / h.

[0369] In a particular embodiment, the spray dryer unit in step b) is a rotary wheel or a two-fluid nozzle atomizer.

[0370] In a particular embodiment, the spray dryer unit in step b) is a rotating wheel pressure swirl single fluid nozzle.

[0371] In a particular embodiment, the spray dryer unit in step b) is a rotary wheel atomizer.

[0372] In a particular embodiment, the spray dryer unit in step b) is a rotary wheel atomizer operating at 10000 to 30000 RPM, or 10000 to 28000 RPM, in particular 15000 to 25000 RPM or 20000 RPM, in particular 18000 to 20000 RPM.

[0373] In a particular embodiment, the rotating wheel atomizer has a diameter of 100 mm and 24 holes.

[0374] In a particular embodiment, the spray dryer unit in step b) is a two-fluid nozzle atomizer, more particularly an internal mixing two-fluid nozzle atomizer, most particularly an internal mixing two-fluid nozzle atomizer in co-current mode.

[0375] In a particular embodiment, the spray dryer unit in step b) allows a water evaporation rate of 5 to 30 kg / h.

[0376] In a specific embodiment, the spray dryer unit in step b) is a GEA Niro Production Minor™ spray dryer from GEA Process Engineering (DK-2860 Soeborg).

[0377] In a particular embodiment, the two-fluid nozzle spray dryer is operated using nitrogen as atomizing gas in step c).

[0378] In a particular embodiment, the two-fluid nozzle spray dryer is operated in step c) at an atomizing gas pressure of 0.5 to 3 bar or 1.5 to 3 bar, in particular 1.5 to 2.6 bar or 2.2 to 2.6 bar, most in particular 2.3 to 2.5 bar.

[0379] In a particular embodiment, the drying gas in step d) is nitrogen.

[0380] In a particular embodiment, the drying gas in step d) is dry nitrogen with a water content below 100 ppm, in particular below 67 ppm.

[0381] In a particular embodiment, the drying gas in step d) is in the form of a gas stream.

[0382] In particular embodiments, the nominal drying gas flow rate in step d) is 100 to 1000 kg / h, particularly 300 to 600 kg / h, most particularly 350 to 450 kg / h, or 400 to 450 kg / h, most particularly in closed cycle mode.

[0383] In particular embodiments, the initial temperature of the drying gas in step d) is from 150 to 200 °C, particularly from 160 to 190 °C or from 160 to 180 °C, most particularly from 170 to 180 °C.

[0384] In a particular embodiment, the outlet temperature of the mixture of water mist and drying gas in step d) is from 70 to 150°C, particularly from 90 to 120°C, most particularly from 100 to 110°C.

[0385] In a particular embodiment, the temperature difference between the initial temperature of the drying gas in step b) and the outlet temperature of the mixture of water mist and drying gas in step d) is between 50°C and 90°C, in particular between 60°C and 80°C.

[0386] In a particular embodiment, the separation in step e) is performed in a cyclone.

[0387] In a particular embodiment, the separation in step e) is carried out in a conical cyclone at a flow rate of 350 to 450 kg / h.

[0388] In a particular embodiment, the separation in step e) is performed in a cyclone with a cut-off point of 5 μm to 10 μm.

[0389] In a particular embodiment, the amorphous etanercept monohydrochloride powder is conveyed from the drying chamber to the cyclone using a drying gas stream in step e).

[0390] In a specific embodiment, the amorphous etanercept monohydrochloride powder is collected in step f) by gravity into a drum.

[0391] In a particular embodiment, the humidified drying gas in step h) is cooled to -10°C to 20°C, particularly 0°C to 10°C, most particularly 5°C to 9°C.

[0392] In a specific embodiment, the method for preparing amorphous etanercept monohydrochloride is carried out using the following method parameters:

[0393] Feed solution: 20% to 25% (w / w) etanercept·HCl·EtOAc 75% to 80% (w / w) water

[0394] Atomizer: Rotating wheel atomizer or two-fluid nozzle

[0395] Atomizer Speed: 10000 to 28000 RPM in case of rotary wheel atomizer

[0396] Atomizing air pressure: 2.2 to 2.6 bar in case of two-fluid nozzles

[0397] Drying gas inlet temperature: 160℃ to 180℃

[0398] Drying gas outlet temperature: 90℃ to 120℃

[0399] Dry gas (nitrogen): 450 kg / h, especially in closed cycle mode

[0400] Condensation temperature (step h): 5°C to 9°C

[0401] In a specific embodiment, the method for preparing amorphous etanercept monohydrochloride is carried out using the following method parameters:

[0402] Feed solution composition: 20% (w / w) etanercept·HCl·EtOAc 80% (w / w) purified water

[0403] Atomization mode: Rotating wheel atomizer or two-fluid nozzle

[0404] Atomizer Speed: 19000RPM in case of rotary wheel atomizer

[0405] Atomization pressure: 2.4 bar in case of two-fluid nozzles

[0406] Drying gas inlet temperature: 175℃

[0407] Drying gas outlet temperature: 105℃

[0408] Dry gas (nitrogen): 400kg / h, closed cycle mode

[0409] Condensation temperature: 5℃ to 9℃

[0410] These optimized conditions enabled excellent yields of 90% to 94% original value and 96% to 100% "corrected value" to be achieved.

[0411] use

[0412] A particular embodiment of the invention relates to a pharmaceutical composition as defined above for use in the treatment of a hyperproliferative disease, in particular for the treatment of cancer.

[0413] A particular embodiment of the invention relates to a method for the treatment of a hyperproliferative disease, in particular for the treatment of cancer, which method comprises administering to a subject a pharmaceutical composition as defined above.

[0414] A particular embodiment of the invention relates to the use of a pharmaceutical composition as defined above for the treatment of a hyperproliferative disease, in particular for the treatment of cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0415] Figure 1 . Flow chart of the production method of the pharmaceutical composition of the present invention.

[0416] Figure 2 .The effect of fillers on tablet hardness depends on the compression force.

[0417] Figure 3 . Scanning electron micrograph (SEM) of particles obtained from composition 11 comprising colloidal silica.

[0418] Figure 4 . Scanning electron micrograph (SEM) of particles obtained from composition 12 without colloidal silica.

[0419] Figure 5 .Effect of binder grade on drug dissolution time.

[0420] Figure 6 The particle size distribution of the material of Example 6C (Batch HQ00003) spray dried using a dual feed nozzle obtained by laser diffraction is bimodal. It is obvious that the particle size distribution is bimodal.

[0421] Figure 7 SEM micrograph of the material of Example 6C (Batch No. HQ00003) spray dried using a dual feed nozzle. A bimodal particle size distribution is evident for nanoparticles and particles with a diameter of 1-10 μm. The sample was sputtered with gold.

[0422] Figure 8 . Flow chart of the spray drying method according to the general procedure of Example 7.

[0423] Fig. 9 Particle size distribution of the material spray dried with a rotating wheel nozzle, i.e. batch BS1506SA03 of Example 13, obtained using a Malvern Mastersizer 2000 equipped with a Hydro 2000S wet dispersion unit (Malvern Instruments Ltd, Malvern / UK) (Table 20). A monomodal particle size distribution is evident.

[0424] Fig.10SEM micrograph of the material obtained using a Zeiss SigmaVP (Carl Zeiss Microscopy GmbH, Oberkochen / DE) and spray dried with a rotating wheel nozzle, i.e. the material of batch BS1506SA07 of Example 13 (Table 20). Spherical particles of almost uniform size are visible.

[0425] Example

[0426] The following examples 1-14 are provided to illustrate the present invention. They should not be considered to limit the scope of the present invention, but are merely representative thereof.

[0427] Example 1

[0428] Ataxetim HCl pharmaceutical composition

[0429] according to Figure 1 As described in the flowchart, and according to the detailed procedures below and the concentrations of the ingredients in Tables 1 to 7 below, the following 15 pharmaceutical compositions were prepared.

[0430] General procedure:

[0431] 1) Filler, (where present) hygroscopic agent and (where present) intragranular disintegrant were sieved by passing through a grinder (mesh size 1.5 mm).

[0432] 2) A premix is ​​prepared by premixing one or more fillers and, where present, a hygroscopic agent together with the API and then introducing the premix into a fluid bed granulator (top spray granulator in drying mode, Diosna Fluid Bed Dryer CCSP150, Diosna Dierks & GmbH, Osnabrück / DE).

[0433] 3) Preparation of granulation solution: Dissolve the binder with water at 25°C and stir until a clear solution is obtained.

[0434] 4) The granulating solution was sprayed onto the fluidized premix in a fluidized bed granulator to obtain wet granules (spraying pressure 3 bar, spraying rate of granulating solution 100 to 125 g / min, nozzle diameter 1.2 mm).

[0435] 5) The obtained wet granules were granulated in a fluidized bed granulator at 65°C with air at 360-560 m 3 Dry for 0-45 (mostly 15-30) minutes at an air flow rate of 2.5 / h.

[0436] 6) The obtained granules were sieved by passing through a grinder (mesh size 1.5 mm).

[0437] 7) The extragranular disintegrant and (where present) glidant were sieved by passing through a grinder (mesh size 1.5 mm).

[0438] 8) preparing a first mixture by mixing an extragranular disintegrant and, if present, a glidant together with the dry granules in a mixer;

[0439] 9) Sieve the lubricant by passing through a grinder (mesh size 1.5 mm).

[0440] 10) preparing a second mixture by mixing the lubricant with the first mixture in a mixer;

[0441] 11) The second mixture was compressed into tablets using a tablet press and punches (API content 100 mg: main compression force 10 kN; API content 200 mg: main compression force 14 kN).

[0442] 12) If applicable, the tablets were coated in a pan coater where an aqueous coating suspension comprising Opadry II 85F240172 PVA based film coating (pink) was sprayed onto the tablets using a nozzle with a diameter of 1.2 mm at a spray pressure of 2 to 2.5 bar.

[0443] 13) If applicable, use air at an inlet temperature of 60°C and 450m 3 The film-coated tablets were dried at an inlet flow rate of / h (fct).

[0444]

[0445] Table 1: Ingredients of compositions 1 to 5 (uncoated tablets).

[0446]

[0447] Table 2: Ingredients of Composition 6 (film-coated tablets).

[0448]

[0449]

[0450] Table 3: Ingredients of Composition 7 (film-coated tablets).

[0451]

[0452]

[0453] Table 4: Ingredients of Composition 8 (film-coated tablets).

[0454]

[0455]

[0456] Table 5: Compositions of compositions 9 and 10 (uncoated tablets) and their tablet cracking properties.

[0457]

[0458]

[0459] Table 6: Compositions of compositions 11 to 13 (uncoated tablets) and their analytical properties.

[0460]

[0461]

[0462] Table 7: Ingredients of compositions 14 and 15 (uncoated tablets). The intragranular matrix composition of composition 8 (GPV0028 / 04) was identical, but the granules were passed through a mill with a mesh size of 1.5 mm in process step 6) according to the general procedure.

[0463] Example 2

[0464] Effect of fillers on pharmaceutical compositions containing etanercept·HCl

[0465] Tablet hardness was measured by compressing the tablets at different compression forces (8-24 kN, every 2 kN). At each compression force, 10 tablets were tested in a tablet hardness tester (Sotax AG, Aesch / CH), and the resulting breaking forces were recorded and averaged. Figure 2 Each point in represents the average hardness of n=10 tablets at the corresponding compression force.

[0466] Figure 2 The compression force / hardness curves of five tablet cores of the present invention are provided:

[0467] GPV0006 / 03 corresponds to composition 1, which comprises 36.27% wt of microcrystalline cellulose, 12.00% wt of pregelatinized starch and 6.00% wt of lactose as fillers (weight ratio 6:2:1).

[0468] GPV0004 / 09 corresponds to composition 3, which comprises 38.50% wt of microcrystalline cellulose and 18.00% wt of mannitol as fillers (weight ratio of about 2:1).

[0469] GPV0004 / 10 corresponds to composition 4, which comprises 38.50% wt of microcrystalline cellulose and 18.00% wt of corn starch as fillers (weight ratio of about 2:1).

[0470] - GPV0004 / 07 corresponds to composition 5, comprising 56.50% wt of microcrystalline cellulose as the sole filler.

[0471] GMP0147 / 03 corresponds to composition 7, which comprises 43.65% wt of microcrystalline cellulose and 12.00% wt of pregelatinized starch as fillers (weight ratio of about 78:22).

[0472] Ideally, at a compression force of 12 to 20 kN (depending on the particle size and punch type), a tablet hardness between 200 N and 350 N is achieved. Therefore, a gentle compression force / hardness curve is preferred. It has been found that compositions 1, 3, 4 and 7 of the present invention meet this requirement ideally. Microcrystalline cellulose (Avicel PH101) as a filler advantageously compensates for the brittleness of etanercept HCl. Microcrystalline cellulose alone as a filler (e.g. in composition 5) does not produce appropriate compression behavior because the compression force / hardness curve is very steep.

[0473] It was further discovered that a combination of microcrystalline cellulose and pregelatinized starch (Starxx 1500) (e.g., Composition 7, as a filler) together with etanercept HCl provided a composition having improved fluidized bed granulation process performance due to the water absorption properties of the pregelatinized starch and also due to improved compression properties compared to a composition comprising only microcrystalline cellulose as a single filler.

[0474] It has further been found that mannitol as a filler (e.g. in composition 3) is less suitable as tablets obtained with mannitol as a filler were found to require very high ejection forces from the tablet press, indicating potential tablet robustness issues (e.g. sticking during tablet compression).

[0475] It was further found that corn starch was less advantageous as a filler (eg in composition 4) because corn starch has inherent elastic mechanical properties which increase the risk of tablet cracking.

[0476] It was further found that lactose as a filler (e.g., composition 12) is less advantageous, as it has been found that tablets obtained with lactose as a filler exhibit increased dissolution times. Moreover, lactose has inherent brittle mechanical properties, which increases the risk of tablet cracking. It has been found that the combination of microcrystalline cellulose and lactose as fillers increases the risk of tablet cracking, as demonstrated by the data provided at the bottom of Table 5.

[0477] To check for tablet flakes, tablets were tested in a standard tablet hardness tester. For each compression force, 10 tablets were tested and the direction of tablet fracture was visually observed. Tablets with no tendency to flake exhibited a vertical fracture direction. The number of tablets exhibiting a horizontal fracture direction (indicating flakes) was recorded.

[0478] The combination of microcrystalline cellulose and pregelatinized starch as fillers showed good stability in the granulation process, produced an acceptable compression force / hardness profile with suitably low tablet attrition at lower hardness and produced acceptable disintegration times at higher hardness.

[0479] Example 3

[0480] Effect of hygroscopic agents on pharmaceutical compositions containing etanercept·HCl

[0481] Compositions 11 and 12 were prepared to evaluate the effect of hygroscopic agents. Granules can be obtained with and without intragranular colloidal silicon dioxide as a hygroscopic agent. However, it was observed that the granulation process without colloidal silicon dioxide as a hygroscopic agent was less robust, i.e. the granules seemed more sensitive to higher spray rates. As can be seen in Table 6, granules without intragranular colloidal silicon dioxide (e.g. Composition 12: d'=285 μm, 16.9% fines) exhibited significantly increased PSD d' (+45%) and reduced fines content (-51%) compared to granules containing 5% wt colloidal silicon dioxide (e.g. Composition 11: d'=197 μm, 25.5% fines). It was further found that the elimination of intragranular colloidal silicon dioxide resulted in lower tablet hardness and higher tablet attrition. It was further found that despite the lower hardness of the tablets, the granules without colloidal silicon dioxide exhibited a 15% higher disintegration time (Composition 12: 14 minutes 43 seconds; Composition 11: 12 minutes 42 seconds). It was further observed that colloidal silica had only a marginal effect on bulk density (composition 12: 0.21 g cm -3 ; Composition 11: 0.25 gcm -3 ).

[0482] Figure 3 A scanning electron micrograph is provided obtained from composition 11. Round particles (amorphous API) are visible, which are delaminated with colloidal silica (small dots on the round particles).

[0483] Figure 4 A scanning electron micrograph obtained from composition 12 is provided. The round API particles are fused with the other excipient matrix. Since the API has high water solubility, it is assumed that the API dissolved during the granulation process and precipitated with the other excipients.

[0484] Colloidal silicon dioxide (Aerosil 200Pharma) as an intragranular hygroscopic agent supports robust fluidized bed granulation process performance.

[0485] Example 4

[0486] Effect of Binders on Pharmaceutical Compositions Containing Etaxel HCl

[0487] As shown in Table 8, the particle size, bulk density and disintegration time of three tablets (Compositions 11, 13 and 5) were investigated. Figure 5 Drug dissolution profiles of these three compositions are provided.

[0488]

[0489]

[0490] Table 8. Analytical properties of compositions 11, 13 and 5.

[0491] In compositions 11 and 13, another binder grade (PVP K30) with lower binding capacity was used compared to composition 5 (PVP K90). Similar process robustness was observed for all three compositions, but the particle size distribution shifted to smaller sizes and higher amounts of fine particles for the compositions containing PVP K30 as binder.

[0492] 2.5% PVP K90 produced larger granule sizes compared to 2.5% and 5% PVP K30. In addition, the amount of fine fractions (fines) in the granules can be significantly reduced by using PVP K90 compared to PVP K30, which is believed to be beneficial in reducing the risk of tablet splitting.

[0493] The effect of binder grade on tablet disintegration time and drug dissolution was not significant. Under similar compression force (about 16 kN) used for tableting, the data showed that PVP K90 (composition 5) resulted in similar dissolution performance as PVP K30 (compositions 11 and 13), as shown in Table 1. Figure 5 Visible in.

[0494] In summary, PVP K90 resulted in larger granules and reduced fines content while maintaining the same beneficial dissolution performance at comparable hardness. Polyvinylpyrrolidone K90 (Collidon K90) as a binder helps to form the appropriate granule size distribution for robust downstream processing performance.

[0495] Example 5

[0496] Effect of lubricants on pharmaceutical compositions containing etanercept·HCl

[0497] The purpose of the lubricant is to lubricate the tablet compression tool to support a robust tablet compression process. Two additional tablets were prepared according to the method of Example 1 to study the effect of the lubricant on the robustness of the tablet compression performance:

[0498] - In contrast to Example 1, the intragranular matrix of composition 14 was sieved through a 2.0 mm sieve in step 6 of the general procedure to obtain coarse granules.

[0499] • In contrast to Example 1, the intragranular matrix of Composition 15 was sieved through a 2.0 mm sieve and through a 0.8 mm sieve in step 6 of the General Procedure to obtain fine particles.

[0500] The particle size distribution of the particles thus obtained was then investigated before mixing with the extragranular matrix provided in Table 9.

[0501]

[0502]

[0503] Table 9. Analytical properties of the particles of compositions 14 and 15 after grinding in process step 6).

[0504] Composition 14 can be considered an extreme example of an overly lubricated final blend because of the coarse particles having a small surface area combined with a magnesium stearate concentration that was above target.

[0505] Composition 15 can be considered an extreme example of a non-lubricated final blend, as the fine particles with a larger surface area are combined with a magnesium stearate concentration that is below target.

[0506] The tablet compression performance, i.e., adhesion and flaking behavior, of compositions 14 and 15 was subsequently evaluated. In all compression runs, the ejection forces were found to be within the normal range for both 100 mg (100-130 N) and 200 mg (about 200 N) tablet sizes, with no observed increase. Interestingly, both extremes showed robust tablet compression performance, indicating a low risk of adhesion and flaking. Robust tablet compression and the absence of microcracks (confirmed by μCT imaging) confirmed that 1% wt of magnesium stearate corresponded to the optimal lubricant concentration in the extragranular matrix for both 100 mg and 200 mg tablet dosage strengths.

[0507] Example 6

[0508] Amorphous etanercept monohydrochloride prepared using a two-fluid nozzle spray dryer

[0509] WO 2013 / 173811 A1 describes various spray drying methods on pages 33-35 (Examples 12A-12C) to produce amorphous etaserti monohydrochloride. Amorphous etaserti monohydrochloride was prepared by spray drying solutions of different educt forms of etaserti monohydrochloride using a two-fluid nozzle spray dryer. The conditions and results are shown in Table 10 below.

[0510]

[0511]

[0512] Table 10: Method parameters and quality attributes for amorphous etanercept monohydrochloride.

[0513] The materials obtained according to Table 10 were further investigated with additional analytical methods. The results obtained in Examples 12A-C for the materials described in WO 2013 / 173811 A1 are described in Tables 11 and 12 below.

[0514]

[0515]

[0516]

[0517] Table 11: Quality attributes of amorphous etanercept monohydrochloride (ND = not determined).

[0518]

[0519] Table 12: Shear cell test of amorphous etanercept monohydrochloride (batch number HQ00010) of Example 6C', measured using an automatic ring shear tester RST-XS (Dr. Dietmar Schulze Schüttgutmesstechnik, Wolfenbüttel, DE).

[0520] The following conclusions were obtained from analytical studies of the materials of Examples 6A, 6A', 6B, 6B', 6C and 6C', which were obtained as described in WO 2013 / 173811 A1, pages 33-35:

[0521] The bulk density of the powder of Example 6C' is 0.262 gcm -3 ; Tap density is 0.423gcm -3 , resulting in a Carr index of 38%, indicating that the material has poor fluidity.

[0522] The shear cell test (ffc about 1.1 at all pre-shear stresses, see Table 12) showed that the powder had very poor flowability. The shear test showed that despite the rounded morphology of the particles, the poor flow was mainly due to the small particle size and high cohesiveness (high cohesiveness) of the particles.

[0523] The particle size analysis of the powder of Example 6C showed a bimodal particle size distribution, where d 90 Less than 8.1 μm (see Figure 6).

[0524] ● Based on optical microscopy and scanning electron microscopy (see Figure 7 ), the material obtained from the powder of Example 6C consisted of round particles of two size ranges: submicron-sized nanoparticles and particles with a diameter of 1-10 μm.

[0525] Example 7

[0526] General procedure for the conversion of etanercept monohydrochloride ethyl acetate solvate to amorphous etanercept monohydrochloride using a rotary wheel spray dryer

[0527] The dried acetasetin monohydrochloride ethyl acetate solvate (typically containing 2% wt-8% wt of EtOAc) is dissolved in purified water at 15°C to 30°C. The resulting solution contains 10%-30% solids by weight, and the solids are then fed to a spray dryer unit (Niro ProductionMinorTM spray dryer from GEA Process Engineering, Soeborg, DK) and atomized in a drying chamber using appropriate rotary wheel atomization conditions or alternatively appropriate two-fluid nozzle atomization conditions. The fine mist produced by the atomizer is mixed with a hot nitrogen stream as a drying gas to induce evaporation of water from the droplets. The feed rate of the solution is adjusted to achieve the desired gas outlet temperature. The drying gas transports the fine particles through the drying chamber to the cyclone. The cyclone separates the powder from the drying gas and collects the powder into a barrel by gravity. The essentially powder-free gas flows into the filter bag housing, where very fine particles are retained in the bag filter. The powder-free gas is cooled in the condenser, where water condensation occurs, and the reheated dry gas is recycled to the drying chamber ( Figure 8 Flowchart of the .

[0528] Example 8

[0529] Preparation of amorphous etanercept monohydrochloride

[0530] Five batches of amorphous etanercept HCl (130710450, 130710451, 130710452, 130810453, 130810454) were prepared according to the general procedure of Example 7, except that batch 130810454 used a two-fluid nozzle spray dryer instead of a rotary wheel spray dryer. The amounts of reactants used, process parameters, and analytical results are shown in Table 13. All five batches were obtained within 1 to 2 hours. Four batches (batch numbers 130710450, 130710451, 130710452, and 130810454) using a rotary wheel atomization mode showed improved processability in subsequent drug product production.

[0531]

[0532]

[0533] Table 13: Method parameters and quality attributes of amorphous etanercept monohydrochloride. *Indicates absence of crystalline API.

[0534] Example 9

[0535] Preparation of amorphous etanercept monohydrochloride

[0536] Five additional batches of amorphous etanercept monohydrochloride (140110401, 140110402, 140110403, 140110404, 140110405) were prepared according to the general procedure of Example 7. The amounts of reactants used, process parameters and analytical results are shown in Table 14.

[0537]

[0538]

[0539] Table 14: Method parameters and quality attributes of amorphous etanercept monohydrochloride. *Indicates absence of crystalline API.

[0540] Example 10

[0541] Preparation of amorphous etanercept monohydrochloride

[0542] Five additional batches of amorphous etanercept monohydrochloride (140110406, 140110407, 140110408, 140110409, 140110410) were prepared according to the general procedure of Example 7. The amounts of reactants used, process parameters and analytical results are shown in Table 15.

[0543]

[0544]

[0545] Table 15: Method parameters and quality attributes of amorphous etanercept monohydrochloride. *Indicates absence of crystalline API.

[0546] Embodiment 11

[0547] Preparation of amorphous etanercept monohydrochloride

[0548] Another batch of amorphous etanercept monohydrochloride (140110411) was prepared according to the general procedure of Example 7. The amounts of reactants used, process parameters and analytical results are shown in Table 16.

[0549]

[0550] Table 16: Method parameters and quality attributes of amorphous etanercept monohydrochloride. *Indicates absence of crystalline API.

[0551] Example 12

[0552] Preparation of amorphous etanercept monohydrochloride

[0553] Three additional batches of amorphous etanercept monohydrochloride (140210412, 140210413, 140210414) were prepared according to the general procedure of Example 7. The amounts of reactants used, process parameters and analytical results are shown in Table 17.

[0554]

[0555]

[0556] Table 17: Method parameters and quality attributes of amorphous etanercept monohydrochloride. *Indicates absence of crystalline API.

[0557] Example 13

[0558] Preparation of amorphous etanercept monohydrochloride

[0559] Twenty additional batches of amorphous etanercept monohydrochloride (140910415-141210426 and BS1506SA01-BS1506SA08) were prepared according to the general procedure of Example 7. The amounts of reactants used, process parameters and analytical results are shown in Tables 18, 19 and 20.

[0560] The process conditions employed, for example in Table 20, enable excellent yields of 90% to 94% "original value" and 96% to 100% "corrected value" to be achieved.

[0561]

[0562]

[0563]

[0564] Embodiment 14

[0565] Characterization of Amorphous Etaxel Monohydrochloride

[0566] The various amorphous etanercept monohydrochloride batches obtained in Tables 18 and 20 of Example 13, prepared using a rotary wheel spray dryer, were further characterized by a shear cell test, which was similar to the characterization of the amorphous etanercept monohydrochloride prepared using a two-fluid nozzle spray dryer in Example 6 (Table 12).

[0567] Similar to the classification used by Jenike (Dietmar Schulze, Pulver und Schüttgüter, 2009 Springer Verlag Berlin / DE), the flow behavior can be defined based on the stream function constant (ffc) as follows:

[0568]

[0569] The larger the stream function constant ffc, that is, the smaller the ratio of the unconfined yield strength (σc) to the consolidation stress (σ1), the better the flow of the bulk solid.

[0570] It is apparent from the data in Table 21 that the amorphous etanercept monohydrochloride prepared using a rotary wheel spray dryer exhibits significantly improved flow behavior (ffc up to 4.0) compared to the amorphous etanercept monohydrochloride prepared using a two-fluid nozzle spray dryer in Example 6C' (Table 12, ffc 1.08).

[0571]

[0572]

[0573] Table 21: Shear cell test of amorphous etanercept monohydrochloride of Table 18 and Table 20 of Example 13, measured using an automatic ring shear tester RST-XS, using a 30 mL shear cell (Dr. Dietmar Schulze Schüttgutmesstechnik, Wolfenbüttel, DE).

[0574] The present invention also includes the following items:

[0575] 1. A pharmaceutical composition comprising an Akt inhibitor and one or more pharmaceutically acceptable excipients selected from fillers, binders and disintegrants.

[0576] 2. The pharmaceutical composition of claim 1, comprising an Akt inhibitor, one or more fillers, a binder and a disintegrant.

[0577] 3. The pharmaceutical composition of any one of items 1 or 2, wherein the intragranular matrix comprises an Akt inhibitor and one or more pharmaceutically acceptable excipients selected from fillers, binders and disintegrants.

[0578] 4. A pharmaceutical composition according to any one of items 1 to 3, wherein the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etaserti) or a pharmaceutically acceptable salt thereof.

[0579] 5. The pharmaceutical composition of any one of items 1 to 4, comprising 50 mg to 1000 mg of an Akt inhibitor.

[0580] 6. A pharmaceutical composition according to any one of items 1 to 5, wherein the amorphous monohydrochloride salt of (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etasertid) is used.

[0581] 7. The pharmaceutical composition of any one of items 1 to 6, comprising one or more fillers selected from microcrystalline cellulose, pregelatinized starch, corn starch, lactose, mannitol, calcium phosphate, hydroxypropyl cellulose, polyethylene glycol, sorbitol, maltodextrin and dextrose.

[0582] 8. The pharmaceutical composition of any one of items 1 to 7, comprising one or two fillers selected from microcrystalline cellulose and pregelatinized starch.

[0583] 9. The pharmaceutical composition of any one of items 1 to 8, comprising one or more binders selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl acetate, polyvinyl alcohol, gelatin and gum arabic.

[0584] 10. The pharmaceutical composition of any one of items 1 to 9, wherein the binder is polyvinylpyrrolidone.

[0585] 11. The pharmaceutical composition of any one of items 1 to 10, comprising one or more disintegrants selected from cross-linked carboxymethylcellulose sodium, crospovidone, sodium starch glycolate, sodium alginate, starch, pectin, cellulose derivatives and cross-linked carboxymethylcellulose calcium.

[0586] 12. The pharmaceutical composition of any one of items 1 to 11, comprising croscarmellose sodium as a disintegrant.

[0587] 13. The pharmaceutical composition of any one of items 1 to 12, further comprising one or more lubricants.

[0588] 14. The pharmaceutical composition of claim 13, comprising one or more lubricants selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, talc, calcium stearate and stearyl alcohol.

[0589] 15. The pharmaceutical composition of any one of items 12 to 14, comprising magnesium stearate as a lubricant.

[0590] 16. The pharmaceutical composition of any one of items 1 to 15, further comprising one or more hygroscopic agents.

[0591] 17. The pharmaceutical composition of claim 16, wherein the hygroscopic agent is intragranular.

[0592] 18. The pharmaceutical composition of claim 17, comprising one or more hygroscopic agents selected from the group consisting of colloidal silicon dioxide, fumed silicon dioxide, non-fumed silicon dioxide, pregelatinized starch, corn starch and cross-linked carboxymethyl cellulose.

[0593] 19. The pharmaceutical composition of any one of items 17 to 18, wherein the hygroscopic agent is colloidal silicon dioxide.

[0594] 20. The pharmaceutical composition of any one of items 1 to 19, further comprising one or more glidants.

[0595] 21. The pharmaceutical composition of claim 20, comprising one or more glidants selected from the group consisting of colloidal silicon dioxide, talc, magnesium stearate, polyethylene glycol, calcium stearate and cetyl alcohol.

[0596] 22. The pharmaceutical composition of any one of items 20 to 21, comprising colloidal silicon dioxide as a glidant.

[0597] 23. The pharmaceutical composition of any one of items 1 to 22, further comprising a film coating.

[0598] 24. The pharmaceutical composition of claim 23, comprising a film coating selected from a PVA-based film coating or a HPMC-based film coating.

[0599] 25. The pharmaceutical composition of any one of items 1 to 24, comprising:

[0600] 20%wt-40%wt of etanercept or a pharmaceutically acceptable salt thereof,

[0601] 20%wt-65%wt of microcrystalline cellulose as filler,

[0602] 0-50%wt of pregelatinized starch as filler,

[0603] 0-10%wt of colloidal silicon dioxide as a hygroscopic agent,

[0604] 1%wt-10%wt of polyvinyl pyrrolidone as a binder,

[0605] 0-5%wt colloidal silicon dioxide as a glidant,

[0606] 3%wt-10%wt of cross-linked carboxymethylcellulose sodium as a disintegrant, and

[0607] 0-5%wt of magnesium stearate is used as a lubricant.

[0608] 26. The pharmaceutical composition of any one of items 1 to 25, comprising:

[0609] 20%wt-40%wt of etanercept free base or etanercept monohydrochloride,

[0610] 40%wt-45%wt of microcrystalline cellulose as filler,

[0611] 10%wt-15%wt of pregelatinized starch as filler,

[0612] 2%wt-4%wt of colloidal silicon dioxide as a moisture absorbent,

[0613] 1.5%wt-3.5%wt of polyvinyl pyrrolidone as a binder,

[0614] 0.5%wt-1.5%wt of colloidal silicon dioxide as a glidant,

[0615] 5%wt-7%wt of cross-linked carboxymethylcellulose sodium as a disintegrant, and

[0616] 0.5%wt-1.5%wt of magnesium stearate is used as a lubricant.

[0617] 27. The pharmaceutical composition of any one of items 1 to 26, wherein the pharmaceutical composition is a tablet, a capsule or a sachet.

[0618] 28. The pharmaceutical composition of any one of items 1 to 26, wherein the pharmaceutical composition is an immediate release film-coated tablet.

[0619] 29. A method for producing particles suitable for further use in the pharmaceutical composition of any one of items 1 to 28, the method comprising the steps of:

[0620] a) optionally sieving the one or more fillers, optionally sieving the disintegrant and, where present, the hygroscopic agent by passing through a grinder;

[0621] b) preparing a premix by premixing the one or more fillers and, where present, the hygroscopic agent together with the API, and then introducing the premix into a fluid bed granulator;

[0622] c) preparing a granulation solution by dissolving the binder in a solvent and then stirring until a clear solution is obtained; alternatively, the binder may be added during the premix preparation of step b), in which case the granulation solution comprises a solvent;

[0623] d) spraying the granulation solution onto the fluidized premix in the fluidized bed granulator to obtain wet granules;

[0624] e) optionally drying the wet granules obtained in the fluid bed granulator.

[0625] 30. A method for producing the pharmaceutical composition of any one of items 1 to 28, the method comprising the following steps:

[0626] a) optionally sieving the one or more fillers and, where present, the hygroscopic agent by passing through a grinder;

[0627] b) preparing a premix by premixing the one or more fillers and, where present, the hygroscopic agent together with the API, and then introducing the premix into a fluid bed granulator;

[0628] c) preparing a granulation solution by dissolving the binder in a solvent and then stirring until a clear solution is obtained; alternatively, the binder may be added during the premix preparation of step b), in which case the granulation solution comprises a solvent;

[0629] d) spraying the granulation solution onto the fluidized premix in the fluidized bed granulator to obtain wet granules;

[0630] e) optionally drying the resulting wet granules in the fluidized bed granulator;

[0631] f) optionally sieving the resulting granules by passing through a grinder;

[0632] g) optionally sieving the disintegrant and, if present, the glidant by passing through a mill;

[0633] h) preparing a first mixture by mixing the disintegrant and, if present, the glidant together with the dry granules in a mixer; alternatively or additionally, the disintegrant may be added during the premix preparation of step b);

[0634] i) optionally sieving the lubricant by passing it through a grinder;

[0635] j) preparing a second mixture by mixing the lubricant with the first mixture in a mixer;

[0636] l) Optionally coat the tablets in a pan coater.

[0637] 31. A method for preparing amorphous etanercept monohydrochloride suitable for use in a pharmaceutical composition according to any one of items 1 to 28, the method comprising the following steps:

[0638] a) dissolving a solvate of etanercept in a solvent;

[0639] b) feeding the resulting feed solution into a spray dryer unit;

[0640] c) atomizing the solution in a drying chamber to produce a mist;

[0641] d) mixing the generated mist with a drying gas, thereby evaporating the solvent;

[0642] e) separating the obtained amorphous etanercept monohydrochloride powder from the drying gas; and

[0643] f) collecting the obtained amorphous etanercept monohydrochloride powder.

[0644] 32. The method of claim 31, further comprising the steps of:

[0645] g) introducing the dry gas from the cyclone into the filter bag housing, where very fine particles are retained in the bag filters;

[0646] h) cooling the drying gas in a condenser to produce solvent condensation;

[0647] i) The re-dried drying gas is reheated and recycled into the drying chamber.

[0648] 33. The method of any one of items 31 to 32, wherein the solvate of etaserti in step a) comprises a solvent selected from the following list in the crystal lattice: methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl propionate, methyl ethyl ketone, 2-pentanone, methyl butyl ketone, methyl isobutyl ketone, diisopropyl ketone, diisobutyl ketone and methyl tert-butyl ether.

[0649] 34. The method of any one of items 31 to 33, wherein the solvate of etaserti in step a) is etaserti monohydrochloride ethyl acetate solvate (etaserti·HCl·EtOAc).

[0650] 35. The process of any one of items 31 to 34, wherein the spray dryer unit in step b) is a rotary wheel or a two-fluid nozzle atomizer.

[0651] 36. The method of any one of items 31 to 35, wherein the method is performed using the following method parameters:

[0652] Feed solution: 20% to 25% (w / w) etanercept·HCl·EtOAc 75% to 80% (w / w) water;

[0653] Atomizer: Rotating wheel atomizer or two-fluid nozzle;

[0654] Atomizer speed: 10000 to 28000 in case of rotary wheel atomizer

[0655] RPM;

[0656] Atomizing air pressure: 2.2 to 2.6 bar in case of two-fluid nozzles;

[0657] Drying gas inlet temperature: 160℃ to 180℃;

[0658] Drying gas outlet temperature: 90℃ to 120℃;

[0659] Dry gas (nitrogen): 450 kg / h, especially in closed cycle mode;

[0660] Condensation temperature (step h): 5°C to 9°C.

[0661] 37. The pharmaceutical composition of any one of items 1 to 28 for use in the treatment of a hyperproliferative disease.

[0662] 38. A method of treating a hyperproliferative disease, the method comprising administering to a subject the pharmaceutical composition of any one of items 1 to 28.

[0663] 39. Use of the pharmaceutical composition of any one of items 1 to 28 in the treatment of a hyperproliferative disease.

[0664] 40. The present invention as hereinbefore described.

Claims

1. A pharmaceutical composition comprising: (i) an intragranular matrix comprising: (a) an Akt inhibitor, wherein the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etaserti) or a pharmaceutically acceptable salt thereof, (b) a filler, wherein the filler is microcrystalline cellulose and pregelatinized starch, (c) a binder, said binder being polyvinyl pyrrolidone, and (d) a hygroscopic agent, wherein the hygroscopic agent is colloidal silicon dioxide; and (ii) an extragranular matrix comprising: (a) a disintegrant, wherein the disintegrant is cross-linked carboxymethyl cellulose sodium; (b) a glidant, said glidant being colloidal silicon dioxide; and (c) a lubricant, wherein the lubricant is magnesium stearate.

2. The pharmaceutical composition of claim 1, wherein the intragranular matrix further comprises a disintegrant.

3. The pharmaceutical composition of claim 2, wherein the disintegrant contained in the intragranular matrix is ​​croscarmellose sodium.

4. The pharmaceutical composition according to any one of claims 1 to 3, comprising 50 mg to 1000 mg of the Akt inhibitor.

5. The pharmaceutical composition of any one of claims 1 to 3, comprising 100 mg to 800 mg of the Akt inhibitor.

6. The pharmaceutical composition of any one of claims 1 to 3, comprising 100 mg to 300 mg of the Akt inhibitor.

7. The pharmaceutical composition of any one of claims 1 to 3, comprising 100 mg, 200 mg or 300 mg of an Akt inhibitor.

8. The pharmaceutical composition of any one of claims 1 to 3, wherein the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etaserti).

9. The pharmaceutical composition of any one of claims 1 to 3, wherein the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (etaserti) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is in an amorphous form.

10. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is a monohydrochloride salt.

11. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is an amorphous monohydrochloride salt.

12. The pharmaceutical composition of any one of claims 1 to 3, further comprising a film coating.

13. The pharmaceutical composition of claim 12, comprising a film coating selected from a PVA-based film coating or a HPMC-based film coating.

14. A pharmaceutical composition consisting of: 20%wt-40%wt of etanercept or a pharmaceutically acceptable salt thereof, 20%wt-65%wt of microcrystalline cellulose as filler, 0-50%wt of pregelatinized starch as filler, 0-10%wt of colloidal silicon dioxide as a hygroscopic agent, 1%wt-10%wt of polyvinyl pyrrolidone as a binder, 0-5%wt colloidal silicon dioxide as a glidant, 3%wt-10%wt of cross-linked carboxymethylcellulose sodium as a disintegrant, and 0-5%wt of magnesium stearate is used as a lubricant.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable salt is in an amorphous form.

16. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable salt is a monohydrochloride salt.

17. The pharmaceutical composition of any one of claims 14 to 16, wherein the pharmaceutically acceptable salt is an amorphous monohydrochloride salt.

18. The pharmaceutical composition according to any one of claims 14 to 16, wherein the %wt of microcrystalline cellulose as filler is 40%wt-45%wt.

19. The pharmaceutical composition of any one of claims 14 to 16, wherein the %wt of pregelatinized starch as filler is 10%wt-15%wt.

20. The pharmaceutical composition of any one of claims 14 to 16, wherein the %wt of colloidal silicon dioxide as a hygroscopic agent is 2%wt-4%wt.

21. The pharmaceutical composition of any one of claims 14 to 16, wherein the %wt of polyvinylpyrrolidone as a binder is 1.5%wt-3.5%wt.

22. The pharmaceutical composition of any one of claims 14 to 16, wherein the %wt of colloidal silicon dioxide as a glidant is 0.5%wt-1.5%wt.

23. The pharmaceutical composition of any one of claims 14 to 16, wherein the %wt of croscarmellose sodium as a disintegrant is 5%wt-7%wt.

24. The pharmaceutical composition of any one of claims 14 to 16, wherein the %wt of magnesium stearate as lubricant is 0.5%wt-1.5%wt.

25. A method for producing particles suitable for further use in a pharmaceutical composition according to any one of claims 1 to 24, the method comprising the steps of: a) optionally sieving the filler(s), optionally sieving the disintegrant and, if present, the hygroscopic agent by passing through a grinder; b) preparing a premix by premixing the one or more fillers and the hygroscopic agent in the presence of the hygroscopic agent together with the API and then introducing the premix into a fluid bed granulator; c) preparing a granulation solution by dissolving the binder in a solvent and then stirring until a clear solution is obtained; alternatively, the binder may be added during the premix preparation of step b), in which case the granulation solution comprises a solvent; d) spraying the granulation solution onto the fluidized premix in the fluidized bed granulator to obtain wet granules; e) optionally drying the wet granules obtained in the fluid bed granulator.

26. A method for producing a pharmaceutical composition according to any one of claims 1 to 24, wherein the pharmaceutical composition is in the form of a tablet, the method comprising the steps of: a) optionally sieving the one or more fillers and the hygroscopic agent, if present, by passing through a grinder; b) preparing a premix by premixing the one or more fillers and the hygroscopic agent in the presence of the hygroscopic agent together with the API and then introducing the premix into a fluid bed granulator; c) preparing a granulation solution by dissolving the binder in a solvent and then stirring until a clear solution is obtained; alternatively, the binder may be added during the premix preparation of step b), in which case the granulation solution comprises a solvent; d) spraying the granulation solution onto the fluidized premix in the fluidized bed granulator to obtain wet granules; e) optionally drying the resulting wet granules in the fluidized bed granulator; f) optionally sieving the resulting granules by passing through a grinder; g) optionally sieving the disintegrant and the glidant, if present, by passing through a mill; h) preparing a first mixture by mixing the disintegrant and the glidant, in the presence of the glidant, together with dry granules in a mixer; alternatively or additionally, the disintegrant may be added during the premix preparation of step b); i) optionally sieving the lubricant by passing it through a grinder; j) preparing a second mixture by mixing the lubricant with the first mixture in a mixer; l) Optionally coat the tablets in a pan coater.

27. A method for preparing a pharmaceutical composition according to any one of claims 11 and 17, the method comprising the following steps for preparing amorphous etanercept monohydrochloride: 1) dissolving a solvate of etanercept in a solvent; 2) feeding the obtained feed solution into a spray dryer unit; 3) atomizing the solution in a drying chamber to generate mist; 4) mixing the generated mist with a drying gas, thereby evaporating the solvent; 5) separating the obtained amorphous etanercept monohydrochloride powder from the drying gas; and 6) collecting the obtained amorphous etanercept monohydrochloride powder, Then, steps a), b), c), d) and e) as defined in claim 25 are carried out, or steps a), b), c), d), e), f), g), h), i), j), k) and l) as defined in claim 26 are carried out.

28. The method of claim 27, wherein the preparation of amorphous etanercept monohydrochloride further comprises the steps of: 7) Dry gas from the cyclone is introduced into the filter bag housing, where very fine particles are retained in the bag filters; 8) cooling the drying gas in a condenser to produce solvent condensation; 9) The re-dried drying gas is reheated and recycled into the drying chamber.

29. The method of any one of claims 27 to 28, wherein the solvate of etaserti in step 1) comprises a solvent selected from the following list in the crystal lattice: methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl propionate, methyl ethyl ketone, 2-pentanone, methyl butyl ketone, methyl isobutyl ketone, diisopropyl ketone, diisobutyl ketone and methyl tert-butyl ether.

30. The method according to any one of claims 27 to 28, wherein the solvate of etaserti in step 1) is etaserti monohydrochloride ethyl acetate solvate (etaserti·HCl·EtOAc).

31. The method of any one of claims 27 to 28, wherein the spray dryer unit in step 2) is a rotary wheel or a two-fluid nozzle atomizer.

32. The method of any one of claims 27 to 28, wherein the method is performed using the following method parameters: Feed solution: 20% to 25% (w / w) of etanercept.HCl.EtOAc 75% to 80% (w / w) water; Atomizer: Rotating wheel atomizer or two-fluid nozzle; Atomizer speed: 10,000 to 28,000 RPM in case of rotary wheel atomizer; Atomizing air pressure: 2.2 to 2.6 bar in case of two-fluid nozzles; Drying gas inlet temperature: 160℃ to 180℃; Drying gas outlet temperature: 90℃ to 120℃; Dry gas (nitrogen): 450 kg / h, especially in closed cycle mode; Condensation temperature (step 8): 5°C to 9°C.

33. The pharmaceutical composition of any one of claims 1 to 3 and 14 to 16, wherein the pharmaceutical composition is for use in the treatment of a hyperproliferative disease.

34. Use of a pharmaceutical composition according to any one of claims 1 to 24 in the preparation of a medicament for the treatment of a hyperproliferative disease.

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