Pharmaceutical preparations

Abstract

The present invention relates to a pharmaceutical formulation comprising the active pharmaceutical ingredient (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, in particular prepared by a process comprising wet granulation, direct compression, or especially roller compaction, and related inventive aspects disclosed herein.

Description

[Technical field]

[0001] The present invention relates to a formulation comprising the active pharmaceutical ingredient (API) (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or a pharma-ceutically acceptable salt thereof, as well as different aspects relating to this formulation and its preparation and further embodiments of the invention, as provided in more detail below and in the claims. [Background technology]

[0002] (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (also known as TNO155) is an orally bioavailable allosteric inhibitor of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2, encoded by the PTPN11 gene), which transmits signals from activated receptor tyrosine kinases (RTKs) to downstream pathways including the mitogen-activated protein kinase (MAPK) pathway, the JAK-STAT pathway, and the phosphoinositol 3-kinase (PI3K)-AKT pathway. SHP2 has also been implicated in immune checkpoint and cytokine receptor signaling. TNO155 has demonstrated efficacy in a broad range of RTK-dependent human cancer cell lines and in vivo xenografts. Further details regarding TNO155, its pharmacological activity and other properties, its preparation, and its salts and polymorphs are given in, for example, the succinate salt of TNO155, the modification (form) H of TNO155 succinic acid (1:1) hemihydrate. A(Example 6) and other polymorphs can be found in WO 2015 / 107495A, WO 2020 / 165734A, WO 2020 / 065452A, and WO 2020 / 065453. In the case of TNO155, the modified H A is more stable than the anhydrous form, and form H A is the active ingredient contained in the formulation of the present invention.

[0003] SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive, autoinhibited conformation stabilized by a network of connections involving residues in both the N-SH2 and PTP domains. Stimulation by, for example, cytokines or growth factors exposes the catalytic site, leading to enzymatic activation of SHP2.

[0004] Mutations in the PTPN11 gene and subsequent mutations in the SHP2 gene have been identified in several human diseases, including but not limited to Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colorectal cancer. Therefore, SHP2 is a very attractive target for the development of novel therapeutic approaches for the treatment of various (especially proliferative) diseases. The pharmaceutical preparations that can be produced according to the present invention meet the demand for inhibiting the activity of SHP2.

[0005] There are three basic methods for the manufacture of tablets: wet granulation and dry granulation, which may be in the form of slug compression or roller compaction, particularly for granules that are subsequently compressed, or directly compressed. The resulting granules may then be compressed into tablets. Dry granulated granules and tablets formed therewith are fundamentally different in structure from wet granulated granules and tablets.

[0006] Wet granulation (WG) involves converting a powder mixture into granules, then mixing with other excipients and compressing the mixture to form tablets. The drug is typically mixed with a granulation fluid (e.g., aqueous or alcoholic) and a binder to form a granulation mixture. Other excipients may also be included in the granulation mixture. Since many drugs have low cohesion, the binder helps to bind the powder particles of the drug together. The granulation mixture is then dried to remove the solvent, resulting in granules in which the drug particles are bound by the binder and other excipients present in the granulation mixture. These granules are mixed with other excipients and compressed into tablets.

[0007] In direct compression (DC), powdered materials can be compressed together directly to form a solid pharmaceutical composition into a tablet, without an intermediate granulation step, avoiding changes in the physical (e.g., crystalline form) and chemical properties of the drug. The tablet ingredients are simply mixed in dry form and compressed in a tablet press.

[0008] Roller compaction (RC) is a specialized mode of providing granules for formulation of solid pharmaceutical compositions (as is, or in capsules, or tablets after compression). Avoiding wetting of ingredients is an advantage over wet granulation during processing, for example when using moisture-sensitive materials. In the roller compaction dry granulation process, powders containing active ingredients and excipients can be agglomerated between the rollers of the compactor. In contrast to wet granulation, roller compaction does not require the use of water or other solvents; therefore, it is particularly suitable for processing compounds that become physically or chemically unstable when exposed to moisture. Solvent granulation using solvents such as ethanol or isopropanol typically requires explosion-proof facilities and solvent recycling capabilities, and therefore can be more challenging and costlier than aqueous granulation. Roller compaction does not require the drying step that is part of the wet granulation process; therefore, it is advantageous for processing compounds that have low melting points or decompose rapidly when heated. A disadvantage is that after being roller compacted, materials tend to lose their binding strength, or "reworkability." Generally, it has been found that the tablet hardness of roller compacted materials is much lower than that of virgin stock under the same tablet compression force. Excessively high roller compaction forces can not only reduce the "reworkability" but also cause discoloration and / or cracking of the compact. Furthermore, very high compression forces can also reduce the dissolution rate of the drug, especially for poorly soluble compounds.

[0009] Tablets produced by roller compaction often have inferior tensile strength compared to tablets produced by wet granulation or direct compression, and generally minimal compression forces should be used and the particle size of the starting powder should be small.

[0010] A second drawback of roll compaction as known in the art is that it can produce uncompacted powders, especially if no liquid binder is used, and can also leave a lot of fines, resulting in lower product yields compared to wet granulation. Summary of the Invention

[0011] Surprisingly, good compaction, flowability and extensibility profiles were found for TNO155 according to the invention (especially its succinate salt form), especially when roller compaction was used. Surprisingly, good friability (the tendency of a solid material to break into small pieces, especially under strong pressure or contact due to friction) was also found. It was possible to find a composition that has a good preservation of this active ingredient under adverse conditions. The use of dry tableting techniques (roller compaction and direct compression) avoids the conversion of TNO155 or its salts (especially the succinate salt as defined below) into different polymorphic forms, which turned out to be a problem when wet granulation was used. However, in some cases, the original form may prevail or be re-established due to remaining crystals acting as seeds. Direct compression and roller compaction showed comparable disintegration times and friability.

[0012] In principle, all tested granulation and compaction techniques and the resulting products performed in a more or less acceptable manner for TNO155. However, despite the above-mentioned expected drawbacks, roller compaction proved to be the most suitable, thus allowing the solid form to be maintained without conversion of the crystalline form. Furthermore, based on stability tests, roller compaction proved to be superior in terms of densification, flowability and extensibility to other manufacturing processes.

[0013] In summary, a feasible pharmaceutical formulation has been established that allows for highly favorable pharmacokinetic and pharmacodynamic properties as well as improved storage, manufacturing, and handling properties of drugs containing TNO155 as the active ingredient.

[0014] TNO155 is known under its chemical name, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, and has the chemical formula (shown in the free base form): [ka]

[0015] The free base or a pharma- ceutically acceptable salt formed from the free base is referred to herein as TNO155 or a pharma- ceutically acceptable salt thereof. TNO155 and its preparation and use are described, for example, in WO 2015 / 107495A; see, for example, Example 69.

[0016] A preferred pharma- ceutically acceptable salt of this compound, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, is its 1:1 succinic acid addition salt. The hemihydrate form of this salt can be represented by the following formula (following the conventions of S / N Guide 2011, European Pharmacopoeia, Figure A-4-15, A-4, VI ​​"Amine Salts", with the amine structure shown on the left (if in amine form) and the acid structure on the right (if not dissociated): [ka]

[0017] This salt, as well as other pharma- ceutically acceptable salts of TNO155, are disclosed, inter alia, in WO 2020 / 065453 A1.

[0018] The most preferred variant of this salt is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinic acid (1:1) hemihydrate form H Aand in particular having at least one, two, three, or all of the peaks at 2θ values ​​of 8.1, 16.3, 17.5, 22.5, and 26.8 (each ±0.2); more preferably having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or all of the peaks at 2θ values ​​(each ±0.2) in the table below, or characterized by an X-ray powder diffraction (XRPD) pattern, or in particular an XRPD diagram as shown in FIG. 1 as shown in WO 2020 / 065453 A1 (see in particular Example 6 of WO 2020 / 065453 A1).

[0019] [Table 1]

[0020] This particular form is also referred to herein as TNO155 BBA.

[0021] All forms (free base TNO155, preferably a pharma- ceutically acceptable salt of TNO155, most preferably TNO155 BBA) fall under the name "Compound A" as used herein.

[0022] In a first embodiment, the present invention relates to a medicament for use in a process for the preparation of ... A or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein in particular the pharmaceutical formulation is manufactured by a process comprising wet granulation, direct compression, or in particular roller compaction.

[0023] In a second embodiment, the present invention relates to a medicament for use in a pharmaceutical composition comprising a medicament of the form H, in particular as defined, for example, in Example 6 of WO 2020 / 065453 A1. A or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein said composition is obtainable or obtained by a process comprising wet granulation.

[0024] In a third embodiment, the present invention relates to a medicament for use in a process for the preparation of ... A or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient; said composition being obtainable or obtained by a process comprising direct compression or roller compaction.

[0025] In a fourth embodiment, the present invention relates to a medicament for use in a pharmaceutical composition comprising a medicament of the form H, in particular as defined, for example, in Example 6 of WO 2020 / 065453 A1. Aor a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient; wherein said composition is obtainable or obtained by a process comprising roller compaction.

[0026] In a fifth embodiment, the present invention relates to a medicament for use in a pharmaceutical composition comprising a medicament of the form H, in particular as defined, for example, in Example 6 of WO 2020 / 065453 A1. A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and an external phase comprising a mixture of pharmaceutically acceptable excipients; wherein the internal phase is preferably prepared by a process comprising wet granulation or roller compaction; and wherein the preparation comprises the steps of mixing the internal phase and the external phase and compressing the resulting material into a tablet, which is optionally coated. In particular, the granules of the internal phase have a discontinuous distribution (the granules may be deformed by pressing the tablet, i.e. a particulate distribution) in the external phase which forms a continuous matrix (except at the outer surface of the tablet where the granular material may also be outside and not completely surrounded by the matrix material). The combination of the internal and external phases may be beneficial with respect to improved disintegration / dissolution properties (especially of tablets), storage robustness, and / or tabletability (the ability of the powder material to transform into a tablet with a given strength under the effect of compression pressure).

[0027] A further embodiment of the present invention relates to a pharmaceutical composition according to any other embodiment mentioned herein, wherein the pharmaceutical composition is a capsule, a sachet, or particularly a tablet, most particularly a coated tablet.

[0028] In a specific embodiment, the present invention relates to a granular granular composition obtainable by roller compaction, in particular of form H as defined, for example, in Example 6 of WO 2020 / 065453 A1. A or a pharmaceutically acceptable salt thereof, and an internal phase having at least one pharmaceutically acceptable excipient, and at least one pharmaceutically acceptable ingredient, and an external phase comprising at least one pharmaceutically acceptable ingredient, wherein in the case of tablets, the external and internal phases are mixed and compressed to form an uncoated tablet (core tablet) or a coated tablet.

[0029] Where mentioned, "available" may be substituted with "obtained."

[0030] When "less preferred" is used, the feature after this word has lower priority than the feature before it.

[0031] Pharmaceutical excipients include: sugar alcohols, such as lactitol, inositol, sorbitol, xylitol or mannitol, especially coarser grades of mannitol, such as mannitol DC (preferred); celluloses, such as microcrystalline cellulose (preferred in the external phase) or cellulose MKGR (e.g. spray-dried) or powdered cellulose; lactose, such as anhydrous lactose or lactose monohydrate (preferred); or isomaltose (preferred), starch, hydrolyzed starch, pregelatinized starch, calcium phosphate (e.g. dibasic calcium phosphate or calcium hydrogen phosphate), calcium sulfate, calcium carbonate, magnesium carbonate, kaolin and maltodextrin; or a diluent (filler) selected from a mixture of two or more such fillers, preferably selected from the group consisting of hydroxyalkylcelluloses, especially hydroxypropylmethylcellulose.

[0032] In one embodiment, the filler is a coarser grade of mannitol.

[0033] In a further embodiment, the bulking agent is mannitol DC.

[0034] Binders selected from sugars or disaccharides, especially sucrose or lactose or somaltose (preferred); copovidone (4-vinylpyrrolidine acetate copolymer) (less preferred); polyvinylpyrrolidone (less preferred); gelatin; celluloses, especially microcrystalline cellulose (most preferred); starches (e.g. pastes, mucilages); pregelatinized starch; gelatin; sugars (e.g. sucrose, glucose, dextrose, molasses, lactose); dextrins; sugar alcohols such as xylitol, sorbitol, polymethacrylates; natural and synthetic gums; cellulose derivatives (including cellulose ethers) such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose (preferred), hydroxypropylcellulose (preferred), hydroxyethylcellulose, ethylcellulose; waxes; magnesium aluminium silicates; and bentonite; or mixtures of two or more such binders.

[0035] In one embodiment, the binder is selected from isomaltose and microcrystalline cellulose.

[0036] In a further embodiment, the binder is microcrystalline cellulose.

[0037] Disintegrants selected especially from effervescent agents; modified cellulose gums; agar; alginic acid; alginates; crosslinked polymers such as croscarmellose sodium (preferred), crospovidone (polyvinylpyrrolidone; less preferred), (especially low-substituted) hydroxypropylcellulose (preferred) or sodium starch glycolate).

[0038] Glidants especially selected from silicon derivatives (e.g. colloidal silicon dioxide, colloidal silica, pyrogenic (=fumed) silica, hydrated sodium aluminosilicate), talc or magnesium carbonate, especially silicon dioxide (especially fumed silica); or mixtures of two or more such glidant lubricants.

[0039] In one embodiment, the glidant is fumed silica.

[0040] For example, lubricants (anti-adherents) such as talc, stearates (e.g., magnesium stearate, calcium stearate, zinc stearate, palmitostearate), stearic acid, hydrogenated vegetable oils, glyceryl behenate, or especially sodium stearyl fumarate, or mixtures of two or more such lubricants.

[0041] In one embodiment, the lubricant is stearyl fumarate.

[0042] The pharmaceutical formulation according to the invention may comprise further pharmaceutical ingredients, for example selected from the group consisting of colorants, absorbents, flavorings, sweeteners, and desiccants, and / or coatings. The capsule according to the invention may be, for example, a hard gelatin capsule or a soft gelatin capsule. The tablet according to the invention may be uncoated or may further carry a coating that dissolves in the gastrointestinal tract.

[0043] Examples of possible coating materials comprise polymers, plasticizers, and pigments, such as one or more components selected from polyvinyl alcohol, hydroxypropyl methylcellulose, talc, polyethylene glycol, lecithin, titanium dioxide, yellow iron oxide, and red iron oxide, such as enteric release, sustained release, or immediate release film coatings, such as OPADRY® II White, OPADRY® II Yellow, OPADRY® II Red, or OPADRY® II Black OPADRY®, OPADRY® II, OPADRY® II 85FOPADRY® QX, OPADRY® SGR, OPADRY® ambII, OPADRY® fx, OPADRY® EZ, OPADRY® TF, or OPADRY® ENTERIC (Colorcon, Ltd, Dartford Kent, England).

[0044] It should be noted that some pharma- ceutically acceptable excipients may be classified into more than one general group (because they may have more than one functional property), and where general groups (e.g., diluents, binders, disintegrants, glidants, and lubricants) and / or their relative or absolute amounts are mentioned, if a particular excipient falls into two groups, the minimum and maximum amounts may be obtained by adding the minimum amount of one general group to the maximum amount of each of the two general groups. Alternatively, an excipient may be deleted from one of the general groups in which it is mentioned, leaving only one occurrence.

[0045] When the following percentages are mentioned in connection with embodiments of the invention, the amounts refer to the entire tablet (including internal and external phases, if specified) or the tablet core (including internal and external phases, if specified) or a single-phase tablet in which no internal and external phases are present, and add up to 100 weight percent (wt%). Coatings add weight and may preferably contribute an additional weight of, for example, 1-20 wt%, for example, 2-10 wt%.

[0046] An embodiment of the present invention comprises the active pharmaceutical ingredient (API) (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (also known as TNO155), in the form of its succinic acid (1:1) salt, in particular in the hemihydrate form of form HA as defined for example in Example 6 of WO 2020 / 065453 A1, preferably in an amount of 5 to 30% by weight (=% by weight based on the weight of the free base whenever referred to herein), or a pharma- ceutical acceptable salt thereof, and at least one pharma-ceutical acceptable excipient, in particular one or two fillers. , a disintegrant, a glidant and a lubricant, preferably one or two fillers selected in particular from the group consisting of mannitol (e.g. in an amount of 10-60% by weight, such as 40-50% by weight) and microcrystalline cellulose (e.g. in an amount of 10-50% by weight, such as 25-38% by weight), a disintegrant, in particular croscarmellose sodium (e.g. in an amount of 1-20% by weight, such as 3-7% by weight), a glidant, in particular fumed silica (e.g. in an amount of 2-5% by weight, such as 1-15% by weight), and a lubricant, in particular magnesium stearate (e.g. in an amount of 0.1-3% by weight, such as 0.2-2% by weight), the tablet being uncoated or coated. In this paragraph, the percentages refer both to excipients in general and to specific excipients.

[0047] Another embodiment of the present invention is a pharmaceutical composition comprising an active pharmaceutical ingredient (API) (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (also known as TNO155), in the form of its succinic acid (1:1) salt, in particular in the hemihydrate form of form HA as defined in Example 6 of WO 2020 / 065453 A1, preferably in an amount of 5 to 40% by weight (=% by weight based on the weight of the free base whenever mentioned herein), such as 10 to 30% by weight; and at least one pharma- ceutically acceptable excipient, in particular one or two fillers, such as microcrystalline cellulose and / or mannitol, preferably in a total amount of 5 to 60% by weight, such as 10 to 50% by weight; in particular 1 to 15% by weight, such as 1 to 5% by weight. the inner phase obtainable by wet granulation, comprising a binder, such as hydroxypropylmethylcellulose and / or hydroxypropylcellulose in an amount of 1 to 15% by weight, such as fumed silica in an amount of 1 to 5% by weight, a glidant, such as fumed silica in an amount of 1 to 15% by weight, such as 1 to 5% by weight, and a disintegrant, preferably sodium starch glycolate or croscarmellose sodium in an amount of 1 to 10% by weight, such as 2 to 5% by weight, and an outer phase which is a mixture comprising a filler, such as microcrystalline cellulose in an amount of 5 to 50% by weight, such as 8 to 25% by weight, a disintegrant, particularly croscarmellose sodium or sodium starch glycolate in an amount of 0.5 to 10% by weight, such as 1 to 3% by weight, a glidant, such as fumed silica in an amount of 1 to 10% by weight, such as 1 to 5% by weight, and a lubricant, such as magnesium stearate in an amount of 0.1 to 3% by weight, such as 0.2 to 2% by weight. The tablets may be coated or uncoated.

[0048] Another embodiment of the present invention relates to the active pharmaceutical ingredient (API) (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (also known as TNO155), in the form of a succinic acid (1:1) salt, in particular the hemihydrate form of form HA as defined for example in Example 6 of WO 2020 / 065453 A1, or a pharma- ceutically acceptable salt thereof; in particular in an amount of 15 to 50 wt.% (=% by weight based on the weight of the free base whenever referred to herein). one or two fillers selected from mannitol, lactose, calcium hydrogen phosphate, and cellulose in an amount of 10-60% by weight, such as 10% by weight; a disintegrant selected from sodium starch glycolate and croscarmellose sodium in an amount of 1-10% by weight, such as 2-5% by weight; a binder such as hydroxypropylmethylcellulose in an amount of 1-15% by weight, such as 1-5% by weight; a glidant such as fumed silica in an amount of 1-10% by weight, such as 1-5% by weight; and a lubricant such as magnesium stearate in an amount of 0.1-3% by weight, such as 0.2-2% by weight. The tablets may be coated or uncoated.

[0049] Another embodiment of the present invention relates to an active pharmaceutical ingredient (API) (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl) in the form of succinic acid (1:1) salt, preferably in an amount of 5 to 40% by weight (=% by weight based on the weight of the free base whenever referred to herein), such as 10 to 30% by weight, in particular the hemihydrate form of form HA as defined for example in Example 6 of WO 2020 / 065453 A1. 5-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (also known as TNO155), or a pharma- ceutically acceptable salt thereof; and preferably in a total amount of 5-90% by weight, such as 10-80% by weight, at least one pharma- ceutically acceptable excipient, in particular one or two fillers, such as microcrystalline cellulose and / or mannitol; optionally in particular hydroxypropyl methylcellulose and / or hydroxypropyl methylcellulose in an amount of 0-15% by weight, such as 0 or 1-5% by weight. or hydroxypropylcellulose; a glidant, such as fumed silica, especially in an amount of 1 to 15% by weight, such as 1 to 5% by weight; a disintegrant, preferably sodium starch glycolate or croscarmellose sodium, especially in an amount of 1 to 10% by weight, such as 2 to 5% by weight; and a lubricant, such as magnesium stearate, especially in an amount of 0.1 to 3% by weight, such as 0.2 to 2% by weight; and an outer phase which is a mixture comprising a filler, such as microcrystalline cellulose, especially in an amount of 2 to 50% by weight, such as 3 to 25% by weight; a disintegrant, particularly croscarmellose sodium or sodium starch glycolate, especially in an amount of 0.5 to 10% by weight, such as 1 to 4% by weight; a glidant, such as fumed silica, especially in an amount of 0.5 to 10% by weight, such as 0.5 to 5% by weight; and a lubricant, such as magnesium stearate, especially in an amount of 0.1 to 3% by weight, such as 0.2 to 2% by weight. The tablets may be coated or uncoated.

[0050] Another embodiment of the present invention relates to a pharmaceutical composition according to any one of the other embodiments, having a dissolution rate of less than 30 minutes, in particular less than 20 minutes, or preferably 15 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes for at least 95% dissolution, measured as described in Example 7.

[0051] Micronized drug substance (TNO155, specifically succinate salt, specifically succinic acid (1:1) hemihydrate form H A It has also been found that micronized APIs with a particle size of 0.2 μm to 1 μm, particularly 0.8 μm, d50=1.0 to 2.0 μm, particularly 1.6 μm, and d90=2.1 μm to 5 μm, particularly 3.1 μm, are micronized APIs with a particle size of 0.2 μm to 1 μm, particularly 0.8 μm. See below for determining particle size.

[0052] Another beneficial effect, especially on tablet hardness and weight uniformity, can be established by using a coarse filler rather than a fine filler, such as, for example, mannitol. Preferably, the mannitol has a particle size, as determined by dynamic image analysis techniques, according to ISO 14488:2007, with a Q3[50%] (volume basis) in the range of 50-250 μm, such as, for example, 100-20 μm.

[0053] The present invention also relates to a method for treating a (particularly proliferative, especially cancer) disease in an animal, particularly a human (= patient), in which modulation of SHP2 activity may prevent, inhibit or ameliorate the pathology and / or symptoms of the disease, the method comprising the step of administering to an animal (particularly in need thereof) a pharmaceutical composition as defined herein comprising a therapeutically effective amount of compound A alone or in simultaneous or sequential combination with one, two or three additional anti-cancer therapeutic agents.

[0054] The invention also relates to a pharmaceutical composition as defined herein comprising compound A for use in a method for the treatment of a disease in an animal in which SHP2 activity may prevent, inhibit or ameliorate the pathology and / or symptoms of the disease, said method comprising the step of administering said salt or salt form to a warm-blooded animal, in particular a human patient.

[0055] The invention also relates to the use of a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease in an animal, particularly a human patient, where SHP2 activity contributes to the pathology and / or symptomology of the disease.

[0056] As previously described in WO 2020 / 065453A1, Src Homolgy-2 phosphatase (SHP2) is a protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signal transduction through the Ras mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3 kinase AKT pathways. SHP2 mediates the activation of Erkl and Erk2 (Erkl / 2, Erk) MAP kinases by receptor tyrosine kinases such as ErbBl, ErbB2, and c-Met.

[0057] SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive conformation and inhibits its own activity through a binding network involving residues in both the N-SH2 and PTP domains. In response to growth factor stimulation, SHP2 binds through its SH2 domains to specific tyrosine phosphorylation sites on docking proteins such as Gab1 and Gab2. This induces a conformational change, leading to the activation of SHP2.

[0058] Mutations in PTPN11 have been identified in several human diseases, including Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colorectal cancers. SHP2 is an important downstream signaling molecule for various receptor tyrosine kinases, including those for platelet-derived growth factor (PDGF-R), fibroblast growth factor (FGF-R), and epidermal growth factor (EGF-R). SHP2 is also an important downstream signaling molecule for the activation of mitogen-activated protein (MAP) kinase pathways, which can lead to cellular transformation, a prerequisite for cancer development. Knockdown of SHP2 significantly inhibited cell proliferation in lung cancer cell lines with SHP2 mutations or EML4 / ALK translocations, as well as EGFR-amplified breast and esophageal cancers. SHP2 is also activated downstream of oncogenes in gastric cancer, anaplastic large cell lymphoma, and glioblastoma.

[0059] Noonan syndrome (NS) and Leopard syndrome (LS) - PTPN11 mutations cause LS (multiple lentigines, electrocardiogram conduction abnormalities, ocular hypertelorism, pulmonary valve stenosis, genital anomalies, growth retardation, sensorineural hearing loss) and NS (congenital anomalies including cardiac defects, craniofacial anomalies, and short stature). Both diseases are part of a family of autosomal dominant syndromes caused by germline mutations in components of the RAS / RAF / MEK / ERK mitogen-activated protein kinase pathway, which is required for normal cell growth and differentiation. Aberrant regulation of this pathway has significant effects on cardiac development in particular, leading to various abnormalities such as valvular septal defects and / or hypertrophic cardiomyopathy (HCM). It has been established that perturbations in the MAPK signaling pathway are central to these diseases, and several candidate genes along this pathway have been identified in humans, including mutations in KRAS, NRAS, SOS1, RAF1, BRAF, MEK1, MEK2, SHOC2, and CBL. The most commonly mutated gene in NS and LS is PTPN11. Germline mutations in PTPN11 (SHP2) are found in approximately 50% of NS patients and in almost all LS patients who share certain features with NS. In NS, the Y62D and Y63C substitutions in the protein are almost invariant and are among the most common mutations. Both of these mutations affect a catalytically inactive conformation of SHP2 without preventing the binding of the phosphatase to its phosphorylated signaling partners.

[0060] Juvenile myelomonocytic leukemia (JMML)-PTPN11 (SHP2) somatic mutations occur in approximately 35% of patients with JMML, a pediatric myeloproliferative disorder (MPD). These gain-of-function mutations are typically point mutations within the N-SH2 domain or within the phosphatase domain that disrupt the autoinhibition between the catalytic and N-SH2 domains, resulting in SHP2 activity.

[0061] Acute myeloid leukemia-PTPN11 mutations have been identified in approximately 10% of childhood acute leukemias, such as myelodysplastic syndromes (MDS); approximately 7% of B-cell acute lymphoblastic leukemia (B-ALL); and approximately 4% of acute myeloid leukemia (AML).

[0062] The NS and leukemic mutations cause amino acid changes located in the interface formed by the N-SH2 and PTP domains in the autoinhibited SHP2 structure, disrupting inhibitory intramolecular interactions and leading to hyperactivity of the catalytic domain.

[0063] SHP2 functions as a positive regulator of receptor tyrosine kinase (RTK) signaling. amp , Her2 amp , FGFR amp , Met amp Cancers that involve translocations / activation of RTKs (i.e., ALK, BCR / ABL) include esophageal, breast, lung, colon, gastric, glioma, and head and neck cancers.

[0064] Esophageal cancer (or oroesophageal cancer) is a malignant tumor of the esophagus. There are various subtypes, mainly squamous cell carcinoma (less than 50%) and adenocarcinoma. Esophageal adenocarcinoma and squamous cell carcinoma have high expression of RTKs. Therefore, the SHP2 inhibitors of the present invention can be employed in innovative therapeutic strategies.

[0065] Breast cancer is a major type of cancer and a leading cause of death in women when patients develop resistance to current drugs. There are four major subtypes of breast cancer: luminal A, luminal B, Her2-like, and triple-negative / basal-like. Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that lacks specific targeted therapies. Epidermal growth factor receptor I (EGFR) has emerged as a promising target in TNBC. Inhibition of Her2 as well as EGFR via SHP2 may be a promising treatment for breast cancer.

[0066] Lung cancer-NSCLC is currently the leading cause of cancer-related deaths, accounting for approximately 85% of lung cancers (mainly adenocarcinoma and squamous cell carcinoma). Although cytotoxic chemotherapy remains an important part of treatment, targeted therapies based on gene mutations such as EGFR and ALK in tumors are likely to be more effective.

[0067] Colon Cancer - Approximately 30%-50% of colorectal tumors are known to harbor KRAS mutations (abnormalities), and BRAF mutations occur in 10%-15% of colorectal cancers. In a subset of patients, where EGFR has been demonstrated to be overexpressed in colorectal tumors, these patients demonstrate good clinical responses to anti-EGFR therapy.

[0068] Gastric cancer is one of the most common types of cancer. Abnormal expression of tyrosine kinases, reflected by abnormal tyrosine phosphorylation in gastric cancer cells, is known in the art. Three receptor-tyrosine kinases, c-met (HGF receptor), FGF receptor 2, and erbB2 / neu, are frequently amplified in gastric cancer. Therefore, reversal of different signal pathways may contribute to the progression of different types of gastric cancer.

[0069] Neuroblastoma is a childhood tumor of the developing sympathetic nervous system that accounts for approximately 8% of childhood cancers. Genomic mutations in the anaplastic lymphoma kinase (ALK) gene are thought to contribute to the pathogenesis of neuroblastoma.

[0070] Squamous cell carcinoma of the head and neck (SCCHN). High levels of EGFR expression have been associated with poor prognosis and resistance to radiation therapy in various cancers, especially in squamous cell carcinoma of the head and neck (SCCHN). Blocking EGFR signaling results in inhibition of receptor stimulation, inhibition of cell proliferation, and reduced invasiveness and metastasis. Therefore, EGFR is a prime target for novel anticancer therapies in SCCHN.

[0071] Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that occur sporadically (~45%), in association with neurofibromatosis type I (~45%), or in association with previous radiation therapy (~10%). Neurofibromatosis type 1 (NF1) is a common neurogenetic syndrome characterized by neurocognitive effects, predisposition to develop benign and malignant tumors, skin and other physical findings, and plexiform neurofibromas (pNFs) in 30-50% of patients. pNFs are precursors to malignant peripheral nerve sheath tumors (MPNSTs) and can themselves be a substantial cause of pain, disfigurement, and functional disability. SHP2 inhibition counteracts the RAS activation effect of NF1 deficiency. NF1 is involved in RAS deactivation, while SHP2 is involved in RAS activation. SHP2 inhibition (SHP2i) and SHP2i combinations may be strategies to overcome, for example, signaling adaptation to MEKi in tumors with RAS hyperactivity due to NF1 deficiency. SHP2i and SHP2i combinations may be strategies to block inhibitor-induced pathway reactivation and identify optimal therapeutic strategies to effectively target NF1-associated MPNSTs.

[0072] The present invention relates to a pharmaceutical composition comprising compound A, which is capable of inhibiting the activity of SHP2.

[0073] In a particular embodiment, the present invention relates to the aforementioned methods and uses, wherein said SHP2 mediated disease is a cancer selected from, but not limited to, JMML; AML; MDS; B-ALL; neuroblastoma; malignant peripheral nerve sheath tumor (MPNST); esophageal; breast cancer; lung cancer; colon cancer; gastric cancer, head and neck cancer. Other diseases are selected from NS; LS; JMML; AML; MDS; B-ALL; neuroblastoma; esophageal cancer; breast cancer; lung cancer; colon cancer; gastric cancer; head and neck cancer, or other cancers as described above or below.

[0074] The pharmaceutical composition of the present invention comprising compound A may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer. For example, TNO155 or a pharma- ceutically acceptable salt thereof as defined above may be administered simultaneously, sequentially or separately in combination with one or more (preferably one, two or three) agents selected from antiproliferative agents, such as anticancer agents or chemotherapeutic agents; mitotic inhibitors, such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine; and other anticancer agents, such as cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine. Examples of combination partners are described in WO 2015 / 107495, WO 2018 / 130928, WO 2020 / 065453, WO 2020 / 165732, WO 2020 / 165733, WO 2020 / 165734, and WO 2021 / 171261, which are referenced herein.

[0075] Such combinations may provide significant advantages in therapy, such as synergistic activity.

[0076] The pharmaceutical compositions of the present invention are preferably solid pharmaceutical compositions for oral administration such as, for example, capsules (which may contain Compound A and at least one pharma- ceutically acceptable excipient in the form of a powder, granules, gel or minitablets), tablets, granules (to be administered by means of a sachet), powders or lyophilized material.

[0077] The pharmaceutical composition preferably comprises or consists of a dosage unit (e.g. tablet, capsule, sachet) for administration three times, twice, in particular once, daily, either consecutively or with an interrupted period. Based on the TNO155 free base content, the amount of Compound A per dosage unit ranges from 1 to 1000 mg, e.g. from 2 to 250 mg, e.g. from 5 to 200 mg, e.g. from 8 to 150 mg, e.g. from 10 to 80 mg. Higher dosage strengths are also possible with the formulations of the invention.

[0078] The pharmaceutical composition may be used in a therapy comprising administering, without limiting possible administration, a total dose of, for example, 1 to 1000 mg, such as 5 to 400 mg, such as 10 to 320 mg, distributed once a day (QD) (e.g., 1 to 320 mg, such as 1.5 to 70 mg), twice a day (BID) (e.g., 10 to 320 mg, such as 30 to 80 mg), or three times a day, or twice a day (BID) in a cycle of 2 weeks on / 1 week off (2w / 1w), or QD (e.g., 30 to 60 mg) in a cycle of 3 weeks / 1 week, or continuously (e.g., 40 or 50 mg QD).

[0079] When a particle size is given as d10, d50 or d90, this refers to the 10th, 50th or 90th percentile, respectively, and means the spherical diameter below which 10%, 50% or 90% of the particles in the sample are smaller, respectively. ISO9276-1:1998(E)(2) specifies that d is interchangeable with x. A The particle size of the drug substance TNO155 in the form is measured by laser diffraction in a cuvette as a wet dispersion using a Sympatec HELOS instrument and using the Fraunhofer diffraction method based on volume distribution.

[0080] Any one or more general features in any embodiment or definition mentioned hereinbefore may be replaced, either independently of other features or collectively, by one of the more specific definitions of such features, thus providing further embodiments of the invention.

[0081] The following examples serve to illustrate the invention without limiting its scope, while at the same time being specific inventive embodiments.

[0082] Any definition of a function / abbreviation defined either in the tables of examples or other text is valid wherever that function / definition appears and is usually defined only once each.

[0083] While any component specifically referred to, for example by trade name, may be substituted, if necessary, with an equivalent component having the same chemical composition, the form referred to is regarded as preferred. [Brief description of the drawings]

[0084] [Figure 1] A graph of dissolution data is shown as % drug release over time for 10 mg and 80 mg dosage units (film coated tablets = FCT). [Diagram 2] 1 shows a flow diagram of a manufacturing process for tablets according to the present invention including roller compaction. [Diagram 3] FIG. 1 shows a comparison of diameter versus volume for two different mannitol grades, Mannitol pH (=Mannitol PH) and Mannitol DC, as determined by dynamic image analysis. [Figure 4] 1 shows the compression force hardness profile of TNO155 10 mg FCT of TNO155 BBA formulation. [Diagram 5] The weight uniformity of approximately 80 mg of FCT is shown, comprising 10 mg of TNO155 free base (in the form of TNO155 BBA).

[0085] Working Example For the HPLC in Table 1, the following conditions were applied: Mobile phase A (%): 0.1% trifluoroacetic acid in water. Mobile phase B (%): water:acetonitrile (50:950 v / v) Column: Aquity HSS T3, Column size: Length 100 mm, inner diameter 2.1 mm, particle size 1.8 μm Flow rate: 0.5mL / min Detection: 220nm Column temperature: 40℃ Autosampler temperature: 22℃ Injection volume: 4μL Run Time: 13.0 minutes Program: Gradient

[0086] [Table 2]

[0087] For the HPLC in Table 2, the following conditions were applied: Mobile phase A: 0.05% TFA aqueous solution: MeOH (98:2%V / V) Mobile phase B: 0.05% TFA aqueous solution: MeOH (5:95%V / V) Ghost Trap: (DS-HP 2.1mm ID, 30mm) Column: Aquity UPLC HSST3 Column size: Length 100 mm, inner diameter 2.1 mm, particle size 1.8 μm Flow rate: 0.3mL / min Autosampler temperature: Room temperature Detection: 225nm Column temperature: 30℃ Injection volume: 2μL Run Time: 30.0 minutes gradient:

[0088] [Table 3]

[0089] Example 1 Chemical Compatibility Testing Binary blends were prepared at 1% w / w drug loading and were found to be compatible with the stability conditions tested (Table 3), with the exception of PVP-K30, which showed some incompatibility after 4 weeks under open conditions at 40° C. / 75% RH. All excipients, except PVP-K30, may still be suitable for pharmaceutical formulations if used in more realistic ratios in the final pharmaceutical formulation (see Example 2).

[0090] Drug substance = TNO155 succinic acid (1:1) hemihydrate, Form H A hereinafter referred to as TNO155 BBA.

[0091] [Table 4]

[0092] [Table 5]

[0093] [Table 6]

[0094] Thus, with the exception of PVPK-30, which is an example of a less preferred component, the components mentioned can be shown to allow acceptable stability.

[0095] Example 2 Compatibility assay - drug loading of approximately 17% w / w Three tablet formulations prepared with a more realistic and conventional drug loading of approximately 17% w / w (Table 4) demonstrated acceptable stability under all conditions (Table 5):

[0096] [Table 7]

[0097] [Table 8]

[0098] Results after 4 weeks for tablet samples in Table 4 under different storage conditions

[0099] [Table 9]

[0100] All three formulations demonstrated acceptable stability under the conditions indicated.

[0101] Example 3 Direct compression based compositions TNO155 succinate (1:1) hemihydrate, also known as TNO155 BBA A For this formulation, direct compression (DC) may be used (TNO155-ORA 0040 and TNO155-ORA-0044 refer to formulations with different batch numbers below; see Table 4).

[0102] [Table 10]

[0103] These core tablets, which exhibit a disintegration time (DT) of less than 4 minutes (always measured herein with 6 tablets, 800 ml water, 37° C.) and a friability after 500 revolutions of less than 0.40% (friability measured in this example with a 2-drum friability tester, sample weight greater than 6.5 g), can be coated using conventional coating operations to produce film-coated tablets.

[0104] Example 4 Wet Granulation (WG) Based Compositions Wet granulation can be used to manufacture TNO155 BBA film coated tablets (FTC). Batch numbers (BN) of wet granulated core tablets TNO155-ORA-0041 and BNTNO155-ORA-0042 (Table 7) showed a disintegration time (DT) of less than 7 minutes and a friability of less than 0.70% after 500 revolutions.

[0105] [Table 11]

[0106] WG-based core tablets could be easily converted to film-coated tablets by conventional coating operations. However, a 30% w / w slurry of TNO155-BBA in water showed conversion to a solid form after 5 hours. Given that the polymorphic landscape of TNO155 is unknown, WG was not pursued further.

[0107] Example 5 Roller Compacted (RC) Based Compositions a) Screening of RC-based compositions: RC was identified as a superior manufacturing process as specific advantages were found, e.g., better density, better flowability, and better scalability, compared to other manufacturing processes. Four compositions (see Table 8) with 16.000% drug loading were prepared, taking into account the following aspects: -Material properties (brittleness / plasticity, water solubility) - Fluidity aspect - Chemical compatibility of TNO155 BBA with excipients - Compressed descriptors of medicines.

[0108] [Table 12]

[0109] BNTNO155-ORA-0047-001, TNO255-ORA-0047-002, TNO-ORA-0047-003, and TNO155-ORA-0047-004 refer to the respective formulations in Table 8.

[0110] These compositions were further compressed with increasing compression force. The resulting compacts were milled to obtain granules, which were tested for flowability and dispersibility and analyzed according to Table 9:

[0111] [Table 13]

[0112] [Table 14]

[0113] Granule dispersibility analysis revealed that BNTNO155-ORA-0047-001 and BNTNO-ORA-0047-003 granules produced relatively clearer dispersions than the other compositions. Composition BNTNO155-ORA-0047-001 emerged as Priority 1 (Lead Prototype) based on the evaluations performed encompassing all the critical parameters mentioned in Table 9.

[0114] Example 7 Achieving improved flow Taking the BNTNO155-ORA-0047-001 composition as a reference, various compositions were screened. However, the flow properties of the blend before the RC step were not improved. Rat-holing is a phenomenon where cohesive powders stick to the walls of a hopper or container and do not move uniformly. Only material from the center flows, resulting in a "rat hole" appearance in the powder. This is an important indication of poor flowability, which became evident during the material discharge stage of the RC process during the development of TNO155.

[0115] To eliminate the rat-hole phenomenon and further improve the flowability, the following aspects were considered to arrive at a further optimized composition using microcrystalline cellulose PH200 (Table 10): the weight percentage of the IG part was increased from 80% w / w to 90% w / w, and the amount of mannitol DC, which has better flowability than cellulose MKGR (comparing mannitol DC with a Carr index of 20.8955% and a Hausner ratio of 1.2642 with cellulose MK-GR with a Carr index of 26.2690% and a Hausner ratio of 1.3560).

[0116] Microcrystalline Cellulose PH 200 (flowability factor 9.13) was chosen instead of Cellulose MK-GR (flowability factor 8.45) to further improve the flowability of the formulation; see Powder Technology 342 (2019) 780-788. Table 8 shows the pharmaceutical formulations using MCC PH 200:

[0117] [Table 15]

[0118] Acceptable compression descriptors were demonstrated by the 10 mg (BN TNO155-ORA-0052-01, not shown) and 80 mg BN TNO155-ORA-0052 core tablets. Adequacy of the tensile strength (greater than 2 MPa) was reflected by a friability of less than 1% after 500 revolutions (2-drum friability tester, sample weight greater than 6.5 g) for both strengths. Porosity was greater than 5% for both strengths and did not affect DT and dissolution rate (Figure 1). BN TNO155-ORA-0052 10 mg and 80 mg FCT showed a release of more than 95% in 15 minutes (0.1 N HCl, 500 ml, basket, 100 rpm).

[0119] Figure 1 shows the dissolution data for the two dosage strengths. Both formulations shown provide good dissolution, greater than 95% within 15 minutes.

[0120] Thus, through judicious formulation changes supported by sound scientific evidence, flow properties were significantly improved. The manufacture of FCT was demonstrated with an acceptable drug release profile.

[0121] Example 8 Technical stability of the composition The disintegration time (DT) of the 10 mg and 80 mg strength core tablets was found to be less than 6 and 8 minutes, respectively, while the average weight of the 10 mg and 80 mg strength core tablets was found to be less than 81 mg and 643 mg, respectively. The satisfactory stability data of 6M is shown in Tables 11-15.

[0122] [Table 16]

[0123] [Table 17]

[0124] [Table 18]

[0125] [Table 19]

[0126] [Table 20]

[0127] [Table 21]

[0128] The data in Tables 11-5 show that all compositions exhibit good stability under the conditions presented.

[0129] Example 9 Manufacturing of TNO155 film-coated tablet (FCT) formulation FIG. 2 shows a flow chart of the process including roller compaction for the TNO155 BBA (TNO 155-BBA in the chart) formulation.

[0130] This process is used to manufacture two compositions (different in the mannitol used) in Table 16 below: Table 16 shows the compositions evaluated in the TNO155-ORA-0073 study.

[0131] [Table 22]

[0132] The process steps depicted in FIG. 2 are set forth in Table 17 below:

[0133] [Table 23]

[0134] Example 10 Mannitol grade selection and its impact on manufacturability and product. A) Certain grades of mannitol provide a better compression hardness profile and better flow properties for the tableting process. Two commonly used mannitol grades (with different particle size distributions) were evaluated. Figure 3 shows the resulting particle size classes.

[0135] Mannitol PH (denoted as Mannitol pH in Figure 3) is much finer than the Mannitol DC grade as measured by dynamic image analysis technique (Camsizer, XT Retsch Technology), and it was also found that the coarser Mannitol grade (Mannitol DC) offers superior flow properties and a good hardness profile suitable for commercial manufacturing. Particle size measurements were performed using a Camsize rXT (Retsch Technology) with angular particles, 3 g, time 3 min 33 s (Mannitol pH) / 1 min 41 s (Mannitol DC), coverage area 0.3%, image rate 1:1, X-Jet, gap width = 4.0 mm, dispersion pressure = 10-0 kPa-. For Mannitol pH = PH), Q3[10.0%] = 0.8 μm, Q3[50.0%] = 30.1 μm, and Q3[90.0%] = 119.1 μm. For mannitol CD, Q3[10.0%] = 79.9 μm, Q3[50.0%] = 162.4 μm, and Q3[90.0%] = 315.8 μm. Q3[x%] is the percentage (percentile value) of particles that reach a given particle diameter based on volume. In the graph in Figure 3, Q3 values ​​are displayed as partial volumes (p3 = fractional volume within a size class) (which sum to Q3) rather than in a cumulative manner (cumulative amount undersized).

[0136] Figure 4 shows that different compression force hardness profiles are observed depending on the mannitol particle size, and is illustrated for the 10 mg TNO155 BBA composition. The rpm refers to the number of revolutions per minute of the tablet press, and does not appear to have a significant effect. It can be concluded that the coarser the material, the higher the average hardness can be achieved with the same compression force. The finer grade of mannitol is Mannitol PH.

[0137] B) Mannitol grade influences core tablet weight uniformity: FIG. 5 shows that the coarser mannitol DC exhibits a narrower, and therefore more defined, weight uniformity than mannitol PH.

[0138] Results are shown as the mean and error bars for 20 tablets weighing approximately 80 mg, each containing 10 mg of TNO155 BBA.

[0139] From A) and B) it can be deduced that coarser grades of mannitol (e.g. Mannitol DC) have a better manufacturability profile than its finer grades. The choice of Mannitol DC was shown to help ensure a better safety profile for the patient, even with tighter control of weight uniformity at low strengths (worse than the scenario for high strengths).

[0140] Example 11: This example provides the composition of the film coated tablets (FCT) evaluated for 10 mg strength of TNO155; see Table 18.

[0141] [Table 24]

Claims

1. 1. A pharmaceutical formulation comprising the active pharmaceutical ingredient (API) (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, particularly manufactured by a process comprising wet granulation, direct compression, or especially roller compaction.

2. 2. The pharmaceutical formulation of claim 1, wherein the API is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine in the form of its succinic acid (1:1) salt in hemihydrate form.

3. 10. The pharmaceutical formulation according to claim 1, obtainable by a process comprising wet granulation.

4. 10. The pharmaceutical formulation according to claim 1, obtainable by a process comprising direct compression or roller compaction.

5. 10. The pharmaceutical formulation of claim 1, comprising an internal phase obtained from granulation of the active pharmaceutical ingredient (API) (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinic acid (1:1) salt in hemihydrate form and one or more pharmaceutically acceptable excipients, and an external phase comprising a mixture of pharmaceutically acceptable excipients, wherein the internal phase is produced by a process comprising wet granulation or roller compaction, and wherein the production comprises compressing the material obtained by mixing the internal and external phases into an optionally coated tablet.

6. 6. The pharmaceutical formulation of claim 5, comprising an internal phase obtainable by roller compaction having the active pharmaceutical ingredient (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinic acid (1:1) salt in the form of a hemihydrate, at least one pharmaceutically acceptable excipient, and at least one pharmaceutically acceptable ingredient, and an external phase comprising at least one pharmaceutically acceptable ingredient.

7. and a lubricant, wherein the active pharmaceutical ingredient (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinic acid (1:1) salt in hemihydrate form in an amount of 5-30% by weight (=percentage by weight) based on the weight of the free base, at least one pharmaceutically acceptable excipient, one or two fillers, a disintegrant, a glidant, and a lubricant, wherein the one or two fillers are selected from the group consisting of mannitol (in an amount of 10-60% by weight, such as 40-50% by weight) and hydroxybenzoates (e.g. 25% by weight).

6. The pharmaceutical formulation of claim 5, wherein the disintegrant is selected from the group consisting of microcrystalline cellulose (e.g. in an amount of 10-50% by weight, such as up to 38% by weight), the disintegrant is croscarmellose sodium (e.g. in an amount of 1-20% by weight, such as 3-7% by weight), the glidant is fumed silica (e.g. in an amount of 1-15% by weight, such as 2-5% by weight), and the lubricant is magnesium stearate (e.g. in an amount of 0.1-3% by weight, such as 0.2-2% by weight); the tablet is uncoated or coated, and the percentages refer to the combination of the inner and outer phases without the coating.

8. 2. A pharmaceutical formulation according to claim 1 in the form of a capsule, a sachet or, in particular, an uncoated or coated tablet.

9. a pharmaceutical composition comprising the active pharmaceutical ingredient (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinate (1:1) in hemihydrate form in an amount of 5 to 40% by weight or 10 to 30% by weight, and at least one pharmaceutically acceptable excipient in a total amount of 5 to 60% by weight or 10 to 50% by weight, and one or two fillers selected from microcrystalline cellulose and mannitol; a binder selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose in an amount of 1 to 15% by weight or 1 to 5% by weight; a glidant fumed silica in an amount of 1 to 15% by weight or 1 to 5% by weight; and sodium starch glycolate.

6. The pharmaceutical formulation of claim 5 in the form of a tablet, comprising an inner phase obtainable by wet granulation, comprising a disintegrant selected from croscarmellose sodium and sodium starch glycolate in an amount of 1-10% or 2-5% by weight, and an outer phase which is a mixture comprising: a filler microcrystalline cellulose in an amount of 5-50% or 8-25% by weight; a disintegrant selected from croscarmellose sodium and sodium starch glycolate in an amount of 0.5-10% or 1-3% by weight; a glidant fumed silica in an amount of 1-10% or 1-5% by weight; and a lubricant magnesium stearate in an amount of 0.1-3% or 0.2-2% by weight, wherein the tablet is uncoated or coated, and the percentages refer to the combination of the uncoated inner phase and the outer phase.

10. the active pharmaceutical ingredient (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinic acid (1:1) salt in the form of a hemihydrate in an amount of 5 to 40% by weight; one or two fillers selected from mannitol, lactose, calcium hydrogen phosphate, and cellulose in an amount of 10 to 60% by weight or 15 to 50% by weight; sodium starch glycolate and croscarmellose sodium 6. The pharmaceutical formulation of claim 5, in the form of a tablet comprising: a disintegrant selected from the group consisting of: a binder hydroxypropyl methylcellulose in an amount of 1 to 15% or 1 to 5% by weight; a glidant fumed silica in an amount of 1 to 10% or 1 to 5% by weight; and a lubricant magnesium stearate in an amount of 0.1 to 3% or 0.2 to 2% by weight, wherein the tablet is uncoated or coated, and the percentages refer to the combined inner and outer phases without the coating.

11. the active pharmaceutical ingredient (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinic acid (1:1) salt in the form of its hemihydrate in an amount of 5 to 40% by weight or 10 to 30% by weight, and at least one pharmaceutically acceptable excipient preferably in a total amount of 5 to 90% by weight or 10 to 80% by weight, with one or two fillers selected from microcrystalline cellulose and mannitol; optionally a binder selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose in an amount of 0 to 15% by weight or 1 to 5% by weight; a glidant fumed silica in an amount of 1 to 15% by weight or 1 to 5% by weight; sodium starch glycolate and croscarmellose sodium 6. The pharmaceutical formulation of claim 5, wherein the pharmaceutical formulation is in the form of a tablet comprising an internal phase obtainable by roller compaction having a selected disintegrant in an amount of 1-10% or 2-5% by weight; and a lubricant magnesium stearate in an amount of 0.1-3% or 0.2-2% by weight, and an external phase which is a mixture comprising 2-50% or 3-25% by weight of a filler microcrystalline cellulose; a disintegrant selected from croscarmellose sodium and sodium starch glycolate in an amount of 0.5-10% or 1-4% by weight; a glidant fumed silica in an amount of 0.5-10% or 0.5-5% by weight; and a lubricant magnesium stearate in an amount of 0.1-3% or 0.2-2% by weight, the tablet being uncoated or having a coating, the percentages referring to the combination of the uncoated internal phase and the external phase.

12. 2. The pharmaceutical formulation of claim 1, wherein the API used for manufacturing the pharmaceutical formulation has particle sizes defined as d10 = 0.2 μm to 1 μm, or 0.8 μm; d50 = 1.0 to 2.0 μm, or 1.6 μm; and d90 = 2.1 μm to 5 μm, or 3.1 μm, as determined by laser diffraction.

13. 10. The pharmaceutical formulation of claim 1, which exhibits 95% dissolution within 15 minutes.

14. 10. The pharmaceutical formulation of claim 1 for use in the treatment of a proliferative disorder.

15. Use of the active pharmaceutical ingredient (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of the pharmaceutical formulation of any one of claims 1 to 13 for the treatment of a proliferative disease.

16. 14. A method of treating a proliferative disease, particularly a cancer disease, in a subject, comprising the step of administering to a subject in need thereof a pharmaceutical formulation according to any one of claims 1 to 13 comprising a therapeutically effective amount of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine or a pharmaceutically acceptable salt thereof, alone or in simultaneous or sequential combination with one, two or three anti-cancer therapeutic agents, wherein modulation of SHP2 activity can prevent, inhibit or ameliorate disease pathology and / or symptoms.

17. 14. A method for preparing the pharmaceutical composition of any one of claims 1 to 13, comprising combining (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient in a process comprising wet granulation, direct compression, or roller compaction.

18. 18. The method of claim 17, comprising the steps of: producing an inner granule phase comprising (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient by roller compaction; mixing granules of the inner granule phase with one or more pharmaceutically acceptable excipients to form an outer phase, thus forming a final mixture of the inner and outer phases; compressing the final mixture into tablet cores; and either leaving the tablets uncoated or coating the tablet cores with a coating material, wherein the pharmaceutical formulation is a tablet.

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