Amorphous solid dispersions comprising natporafenib

Abstract

The invention relates to the field of pharmacy, in particular to a pharmaceutical composition containing N (3-(2-(2-hydroxyethoxy)-6-morpholinopyridine-4-yl)-4-methylphenyl)-2-(trifluoromethyl) isonicotinamide or pharmaceutically acceptable salt of the N (3-(2-(2-hydroxyethoxy)-6-morpholinopyridine-4-yl)-4-methylphenyl)-2-(trifluoromethyl) isonicotinamide. The invention also provides methods for preparing the pharmaceutical compositions for oral administration and methods of treatment with the pharmaceutical compositions.

Description

[0001] Cross-reference

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 370,989, filed Aug. 10, 2022; the application is hereby incorporated herein by reference in its entirety. Field of the Invention

[0003] The present invention provides a solid amorphous dispersion comprising N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (Compound A) or a pharmaceutically acceptable salt thereof and one or more stabilizing polymers. The present invention also provides a pharmaceutical composition or dosage form comprising the amorphous solid dispersion, methods for preparing the same, and methods of treatment using the amorphous solid dispersion. The present invention also provides these pharmaceutical compositions for oral administration. Background of the Invention

[0004] The RAS / RAF / MEK / ERK or MAPK pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Dysregulation of this pathway underlies many tumorigeneses. Aberrant signaling or inappropriate activation of the MAPK pathway is present in multiple tumor types, including melanoma, lung cancer, and pancreatic cancer, and can occur through several different mechanisms, including mutations in RAS and BRAF. RAS is a superfamily of GTPases and includes KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), which is a regulated signaling protein that can be turned on (activated) by various single point mutations, which are referred to as gain-of-function mutations. The MAPK pathway is frequently mutated in human cancers, with KRAS and BRAF mutations being the most common (about 30%).

[0005] N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (Compound A) was initially described in WO 2014 / 151616 as the compound of Example 1156. It is a Raf inhibitor, particularly a CRAF and BRAF inhibitor, and has the structure of Formula I:

[0006]

[0007] WO / 2020 / 230028 describes various crystalline forms of the compound of Formula I or Compound A, including monohydrate H A form. Compound A is also referred to as “naporafenib”.

[0008] Compound A can be used for treating various cancers, especially cancers with MAPK pathway alterations, such as KRAS-mutant NSCLC (non-small cell lung cancer), KRAS-mutant pancreatic cancer (e.g., KRAS-mutant pancreatic ductal adenocarcinoma (PDAC)), KRAS-mutant CRC (colorectal cancer), and NRAS-mutant melanoma.

[0009] Compound A needs to be formulated into a pharmaceutical composition, especially an oral pharmaceutical dosage form, so that the therapeutic benefits of the compound can be delivered to patients in need. The physicochemical properties of the therapeutic compound pose challenges to addressing this need. Compound A has poor solubility in aqueous media and high permeability, which may lead to potential solubility and bioavailability issues that need to be addressed when developing a pharmaceutical dosage form containing naporafenib. Accordingly, an object of the present invention is to provide exemplary solutions for manufacturing a pharmaceutical composition containing naporafenib, which is in the form of a solid oral dosage form that can be ingested by patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1A Depicts the particulate morphology of the drug substance of Compound A as the free base - anhydrate (NXA).

[0011] Figure 1B Depicts the particulate morphology of the drug substance of Compound A as the free base - monohydrate (NXB).

[0012] Figure 2 Illustrates a representative process flow diagram for manufacturing 600 mg / g Compound A (API) particles and adding extragranular components for manufacturing film-coated tablets of Compound A (API). SUMMARY OF THE INVENTION

[0013] Since each active pharmaceutical ingredient (API) has its own physical, chemical, and pharmacological properties, a suitable pharmaceutical composition and dosage form must be designed separately for each new API.

[0014] For Raf inhibitors, such as N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (Compound A), as its pharmaceutically acceptable salt or as the free base, designing a pharmaceutical composition, a pharmaceutical dosage form, and a commercially viable method for preparing the pharmaceutical composition is challenging. This Raf inhibitor is difficult to formulate due to its physicochemical properties, e.g., low solubility, high permeability, and being prone to degradation under certain pH conditions and temperatures. These properties affect the pharmacokinetics, bioavailability, and manufacturing methods of the formulations containing the Raf inhibitor of the present invention.

[0015] Accordingly, there is a need to develop a suitable and robust solid pharmaceutical composition to overcome the above problems. The present invention provides a pharmaceutical composition having enhanced drug dissolution and increased absorption. The pharmaceutical composition can also improve bioavailability and / or reduce inter-patient variability. In addition, the present invention provides a method for manufacturing the pharmaceutical composition, which method is easy to scale up, is a robust processing method, and has economic advantages.

[0016] It is an object of the present invention to provide a formulation of compound A that minimizes the size and / or number of tablets or capsules required for a therapeutically effective dose, desirably fewer than 4 tablets or capsules, more preferably only one or two tablets or capsules.

[0017] With the goal of increasing the therapeutic potential of compound A, the inventors have attempted to increase the therapeutic potential by improving the bioavailability of compound A in a formulation that allows for a sufficiently high drug load (e.g., greater than 5%). In different embodiments, the drug load will be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80%. It will be appreciated that the greater the drug load, the greater the likelihood of instability. Therefore, it is not an easy task to achieve an increase in drug load while maintaining the physical and chemical stability of the resulting drug product.

[0018] The inventors have found that solid dispersion formulations, such as polymer-stabilized amorphous solid dispersion (PSASD) formulations, address one or more of the above objectives.

[0019] The inventors have unexpectedly found that the therapeutic potential of compound A can be increased by formulating compound A as an amorphous solid dispersion with one or more stabilizing polymers. The amorphous solid dispersions of the present invention can confer greater solubility, faster dissolution rates, and improved bioavailability to compound A. It has been found that an amorphous solid dispersion formulation of compound A with the stabilizing polymer hypromellose is particularly suitable for producing a physically and chemically stable pharmaceutical composition at high drug loads of compound A (e.g., up to 80%). The inventors have also found that, compared to compound A in the anhydrous form, an amorphous solid dispersion formulation prepared with compound A in the monohydrate form can double the drug load in the solid dispersion (e.g., from about 30% to 60%) and reduce the tablet size (e.g., by about 70%).

[0020] Given the above difficulties and considerations, it is not an easy task to find a stable pharmaceutical composition that increases the solubility and bioavailability of compound A and is suitable for manufacturing on a commercial scale.

[0021] The aspects, advantageous features, and preferred embodiments of the present invention summarized in the following items contribute to solving the object of the present invention separately or in combination.

[0022] Item A1. An amorphous solid dispersion comprising Compound A or a pharmaceutically acceptable salt thereof and one or more stabilizing polymers, wherein the weight ratio of Compound A or a pharmaceutically acceptable salt thereof to one or more stabilizing polymers is from about 5:95 to about 90:10, about 40:60, about 80:20; preferably about 60:40.

[0023] Item A2. The amorphous solid dispersion according to Item A1, wherein the amorphous solid dispersion is prepared by spray drying, co-grinding, hot melt extrusion, freeze drying, rotary evaporation, solvent evaporation, co-precipitation, lyophilization, or any suitable solvent removal method. Preferably, the amorphous solid dispersion is prepared by hot melt extrusion.

[0024] Item A3. The amorphous solid dispersion according to Item A1, wherein the amorphous solid dispersion is prepared from Compound A in an amorphous form, a crystalline form, or a mixture thereof.

[0025] Item A4. The amorphous solid dispersion according to Item A3, wherein the amorphous solid dispersion is prepared from Compound A in a crystalline form.

[0026] Item A5. The amorphous solid dispersion according to Item A4, wherein the amorphous solid dispersion is prepared from Compound A in an anhydrous crystalline form.

[0027] Item A6. The amorphous solid dispersion according to Item A5, wherein the amorphous solid dispersion is prepared from the anhydrous form A of Compound A.

[0028] Item A7. The amorphous solid dispersion according to Item A4, wherein the amorphous solid dispersion is prepared from Compound A in a hydrate crystalline form (e.g., monohydrate crystalline form).

[0029] Item A8. The amorphous solid dispersion according to Item A7, wherein the amorphous solid dispersion is prepared from the Compound A monohydrate form H of Compound A A prepared.

[0030] Item A9. The amorphous solid dispersion according to Item A1, wherein the one or more stabilizing polymers are selected from polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone (crosslinked povidone or PVP-XL), hydroxypropylcellulose (HPC), low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC-AS), hydroxypropylmethylcellulose phthalate (HPMC-P), carboxymethylcellulose, croscarmellose sodium (NaCMC), methylcellulose, hydroxyethylcellulose, carboxyethylcellulose, carboxymethylcellulose, carboxymethylhydroxyethylcellulose, polyethylene glycol (PEG), polyvinyl alcohol, polyvinylpyrrolidone-vinyl acetate copolymer (copovidone or PVP / VA), polyvinyl alcohol-polyethylene glycol copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyacrylate, polymethacrylate or a mixture thereof.

[0031] Item A10. The amorphous solid dispersion according to Item A9, wherein the one or more stabilizing polymers are polyvinylpyrrolidone (PVP) or polyvinylpolypyrrolidone (crosslinked povidone or PVP XL), preferably poly(vinylpyrrolidone-co-vinyl acetate 60:40 (PVP VA64) or PVP K30.

[0032] Item A11. The amorphous solid dispersion according to Item A9, wherein the one or more stabilizing polymers are croscarmellose sodium (NaCMC, Ac-Di-Sol) or low-substituted hydroxypropylcellulose (L-HPC).

[0033] Item A12. The amorphous solid dispersion according to Item A9, wherein the one or more stabilizing polymers are polymethacrylate, preferably L100 (copolymer of methacrylic acid and methyl methacrylate (1:1)) or L100-55 (poly(methacrylic acid, ethyl acrylate) 1:1).

[0034] Item A13. The amorphous solid dispersion according to Item A9, wherein the one or more stabilizing polymers are hydroxypropylmethylcellulose (HPMC), preferably HPMC 2910.

[0035] Item A14. The amorphous solid dispersion according to Item A9, wherein the one or more stabilizing polymers are hydroxypropylmethylcellulose acetate succinate (HPMC-AS), preferably HPMC-AS-L, HPMC-AS-M or HPMC-AS-H.

[0036] Item A15. The amorphous solid dispersion according to Item A14, wherein the one or more stabilizing polymers are a mixture of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

[0037] Item A16. The amorphous solid dispersion according to Items A1 to A15, which further optionally comprises one or more pharmaceutically acceptable excipients selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, basic stabilizers, colorants, flavorants, preservatives, and combinations thereof.

[0038] Item A17. The amorphous solid dispersion according to Items A1 to A16, which further comprises a glidant selected from silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose fatty acid ester, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof; preferably, the glidant is silica, more preferably colloidal silica.

[0039] Item A18. The amorphous solid dispersion according to Items A1 to A16, which further comprises a solubilizer selected from polyoxyethylene alkylaryl ethers, polyethylene glycol fatty acid esters, D-α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid esters, alkyl sulfates or sulfonates (such as sodium dodecyl sulfate or sodium dioctyl sulfosuccinate), lecithin, polyethoxylated castor oil, and mixtures thereof.

[0040] Item A19. The amorphous solid dispersion according to Items A1 to A18, wherein the amount of Compound A present is about 1% to about 90% (w / w), about 10% (w / w) to about 85% (w / w), preferably about 15% (w / w) to about 80% (w / w), about 20% (w / w) to about 75% (w / w), or about 30% (w / w) to about 60% (w / w) of the dispersion.

[0041] Item A20. The amorphous solid dispersion according to Items A1 to A19, wherein the ratio of the amount by weight of Compound A to the amount by weight of the one or more stabilizing polymers in the dispersion is about 5:95 to 90:10, preferably about 40:60, about 60:40, or about 80:20.

[0042] Item A21. A pharmaceutical composition, which comprises the amorphous solid dispersion according to Items A1 to A20 and optionally one or more pharmaceutically acceptable excipients, and the one or more pharmaceutically acceptable excipients are selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, basic stabilizers, colorants, flavoring agents, preservatives and combinations thereof.

[0043] Item A22. The pharmaceutical composition according to Item A21, wherein the pharmaceutical composition is in the form of tablets, capsules, cachets, beads, granules, oral suspensions, oral solutions or microemulsions, preferably in the form of tablets.

[0044] Item A23. The pharmaceutical composition according to Items A21 to A22, wherein the pharmaceutical composition contains about 10 mg to about 300 mg of Compound A, preferably 50 mg, 100 mg, 200 mg or 300 mg of Compound A.

[0045] Item A24. The pharmaceutical composition according to Claims A21 to A23, wherein the pharmaceutical composition is in the form of tablets or capsules, and it contains: (a) an amorphous solid dispersion of Compound A, wherein the amorphous solid dispersion is in the form of granules, (b) at least one intra-granular excipient, (c) at least one extra-granular excipient, and (d) optionally, a coating.

[0046] Item A25. The pharmaceutical composition according to Item A24, wherein the extra-granular excipient contains a diluent, and the diluent is selected from microcrystalline cellulose, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, powdered cellulose, dextrate, dextrin, glucose excipient, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar confectioner and combinations thereof, preferably wherein the diluent is lactose, microcrystalline cellulose or a mixture of lactose and microcrystalline cellulose.

[0047] Item A26. The pharmaceutical composition according to Items A24 to A25, wherein the extra-granular excipient further contains a disintegrant, and the disintegrant is selected from sodium carboxymethylcellulose cross-linked, low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpolypyrrolidone (cross-linked povidone), sodium bicarbonate, sodium starch glycolate, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch and mixtures thereof, preferably wherein the disintegrant is selected from sodium carboxymethylcellulose cross-linked, sodium bicarbonate and cross-linked povidone, and more preferably wherein the disintegrant is sodium carboxymethylcellulose cross-linked.

[0048] Item A27. A method for preparing a pharmaceutical composition according to Items A21 to A24, comprising the steps of: mixing compound A or a pharmaceutically acceptable salt thereof or its amorphous form or its crystalline form with one or more stabilizing polymers and optionally one or more pharmaceutically acceptable excipients; heating the mixture to form a melt; extruding the melt; cooling the melt to form an amorphous solid dispersion, and optionally granulating the amorphous solid dispersion and / or optionally compressing the amorphous solid dispersion or the particles of the amorphous solid dispersion with one or more pharmaceutically acceptable excipients for further processing to form a composition suitable for dosage forms such as tablets and capsules. Preferably, the amorphous solid dispersion is ground to form particles.

[0049] Item A28. A pharmaceutical composition according to any one of Items A21 to A26, for use as a medicament.

[0050] Item A29. A pharmaceutical composition according to any one of Items A21 to A26, for the treatment of cancer.

[0051] Item A30. A pharmaceutical composition according to any one of Items A21 to A26, for the treatment of cancer, particularly for the treatment of cancers with MAPK pathway alterations, such as KRAS-mutant NSCLC (non-small cell lung cancer), KRAS-mutant pancreatic cancer (e.g., KRAS-mutant pancreatic ductal adenocarcinoma (PDAC)), KRAS-mutant CRC (colorectal cancer), and NRAS-mutant melanoma.

[0052] Item A31. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to any one of Items A21 to A26.

[0053] Item A32. The method according to A30, wherein the cancer has a MAPK pathway alteration, such as KRAS-mutant NSCLC (non-small cell lung cancer), KRAS-mutant pancreatic cancer (e.g., KRAS-mutant pancreatic ductal adenocarcinoma (PDAC)), KRAS-mutant CRC (colorectal cancer), and NRAS-mutant melanoma. Detailed Description

[0054] As used herein, the term "Compound A" refers to N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, or a pharmaceutically acceptable salt thereof.

[0055] As used herein, unless the context clearly indicates otherwise, the term "Compound A" refers to N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide as the free base. Reference to the "free base" of Compound A or the "free form" of Compound A means that Compound A is present as the free base and not as a salt of Compound A.

[0056] In some aspects, the amorphous form of the free base of Compound A, the crystalline form of the free base of Compound A, and mixtures of the amorphous and crystalline forms of Compound A can be used to prepare amorphous solid dispersion formulations of Compound A of the present invention.

[0057] As used herein, the term "amorphous" refers to a solid form of a compound that is substantially not crystalline. Amorphous compounds do not have long-range order and do not exhibit a distinct X-ray diffraction pattern with reflections.

[0058] In one embodiment, the amorphous solid dispersion is prepared from Compound A in crystalline form. In one embodiment, the crystalline form of Compound A used to prepare the amorphous solid dispersion of the present invention is crystalline anhydrate Form A.

[0059] Anhydrate Form A is referred to as "Form A" and is characterized in WO / 2020 / 230028, which is hereby incorporated in its entirety. It can be prepared as described in Example 2 of WO / 2020 / 230028.

[0060] When measured using CuKα radiation, anhydrate Form A of Compound A exhibits an X-ray powder diffraction pattern having at least one, two, or three characteristic peaks at angles of 5.8° ± 0.2°, 11.7° ± 0.2°, and 14.8° ± 0.2° expressed as °2-Theta (°2θ). In another embodiment, when measured using CuKα radiation, polymorphic Form A exhibits at least one, two, or three characteristic peaks at angles of 5.8° ± 0.2°, 11.7° ± 0.2°, 14.8° ± 0.2°, 15.2° ± 0.2°, and 18.7° ± 0.2°. In another embodiment, when measured using CuKα radiation, polymorphic Form A exhibits at least one, two, three, four, or five characteristic peaks at angles of 5.8° ± 0.2°, 10.0° ± 0.2°, 11.7° ± 0.2°, 12.6° ± 0.2°, 13.1° ± 0.2°, 14.8° ± 0.2°, 15.2° ± 0.2°, 18.7° ± 0.2°, 20.2° ± 0.2°, and 25.1° ± 0.2°.

[0061] In another embodiment, the crystalline form of Compound A (free base) is the crystalline monohydrate form H of Compound A A .

[0062] The crystalline monohydrate form H of Compound A A is described in WO / 2020 / 230028, which is hereby incorporated in its entirety, and can be prepared according to the method described in Example 8 of WO / 2020 / 230028. In one embodiment, when measured using CuKα radiation, the monohydrate form H A exhibits an X-ray powder diffraction pattern having at least one, two or three characteristic peaks at angles of 7.3° ± 0.2°, 10.7° ± 0.2° and 23.0° ± 0.2° expressed as °2-Theta (°2θ). In another embodiment, when measured using CuKα radiation, the monohydrate form H A exhibits at least one, two or three characteristic peaks at angles of 7.3° ± 0.2°, 10.7° ± 0.2°, 16.3° ± 0.2°, 16.7° ± 0.2° and 23.0° ± 0.2°. In another embodiment, when measured using CuKα radiation, the monohydrate form H A exhibits at least one, two, three, four or five characteristic peaks at angles of 7.3° ± 0.2°, 10.7° ± 0.2°, 16.3° ± 0.2°, 16.7° ± 0.2°, 17.4° ± 0.2°, 23.0° ± 0.2°, 24.3° ± 0.2°, 25.3° ± 0.2°, 28.3° ± 0.2° and 32.0° ± 0.2°.

[0063] The crystalline monohydrate form H of Compound A A may be characterized in that its X-ray powder diffraction pattern has at least one, two, three, four or five peaks, and the at least one, two, three, four or five peaks have a refractive angle 2theta (θ) value selected from 7.3, 10.7, 16.3, 16.7, 17.4, 23.0, 24.3, 25.3, 28.3, 32.0, wherein the value is ±0.2° 2θ. The crystalline monohydrate form H of Compound A A may also be characterized in that its differential scanning calorimetry curve contains an endothermic event from about 35°C to 135°C and starts dehydrating at about 94°C. The crystalline monohydrate form H of Compound A A may also be characterized in that when heated from 30°C to 300°C at a rate of 20°C / minute, its thermogravimetric analysis curve shows a mass loss of no more than 3.7 wt% between about 43°C and 135°C.

[0064] Use the monohydrate H of compound A A to prepare the amorphous solid dispersion of the present invention, and an oral dosage form with a higher drug load can be obtained compared to other solid forms that do not use the monohydrate H of compound A A (e.g., the anhydrate HA of compound A) as starting materials.

[0065] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic reactions, other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0066] The terms "pharmaceutical composition", "drug product", "drug dosage form", "dosage form", "pharmaceutical preparation", etc. refer to a pharmaceutical composition that can be administered to a patient in need of treatment, which can be in any conventional formulation, such as in the form of powder, granule, pill, capsule, tablet, solution, suspension, or patch, etc.

[0067] The term solid dispersion generally refers to a solid-state system containing at least two components, where one component is substantially uniformly dispersed in the other components. For example, a solid dispersion can be a dispersion of one or more active ingredients in a solid inert carrier or matrix, prepared by melting, solvent, or melt-solvent methods. Although not wishing to be bound by theory, in a solid dispersion, the drug can exist in a molecular state, colloidal state, metastable state, or amorphous state. The formation of a molecular dispersion can provide a method to reduce the drug particle size to near the molecular level (i.e., without particles). When the polymer dissolves, the drug is exposed to the dissolution medium in the form of molecules or fine particles, which are amorphous and can dissolve and be absorbed faster than larger crystalline particles.

[0068] The term "solid dispersion" refers to a dispersion of a compound, especially a drug substance or an active pharmaceutical ingredient (API), in a polymer or a carrier.

[0069] The term "amorphous solid dispersion" refers to a substantially non-crystalline molecular dispersion of a compound, especially a drug substance or an API, in a polymer or a carrier. Before preparing the solid dispersion, the compound can be in an amorphous form, a crystalline form, or a mixture.

[0070] An amorphous solid dispersion using one or more polymers to disperse a drug substance is also called a polymer-stabilized amorphous solid dispersion (PSASD). A PSASD formulation is a thermodynamically unstable solid-state system in which one or more active ingredients are substantially uniformly dispersed in the other components of the formulation and are stabilized using one or more polymers. In one embodiment, the amorphous solid dispersion of the present invention can be prepared from compound A in a crystalline form.

[0071] In one embodiment, the amorphous solid dispersion of the present invention can be prepared from Compound A in an anhydrous crystalline form.

[0072] In one embodiment, the amorphous solid dispersion of the present invention can be prepared from Compound A in anhydrous crystalline form A.

[0073] In one embodiment, the amorphous solid dispersion of the present invention can be prepared from Compound A in a monohydrate crystalline form.

[0074] In one embodiment, the amorphous solid dispersion of the present invention can be prepared from Compound A in monohydrate crystalline form monohydrate form H A of Compound A.

[0075] Method for preparing a solid dispersion

[0076] It has been found that the solid dispersion formulation according to the present invention can be used to improve bioavailability by increasing the solubility of a low-solubility active agent such as Compound A.

[0077] Amorphous solid dispersions are high-energy formulations and pose additional challenges due to their inherently thermodynamically unstable nature. Therefore, their successful development depends to a large extent on the understanding of the specific interactions that stabilize them (Serajuddin, A.T.M.J. Pharm. Sci. 1999, 88, 1058 - 1066; Janssens, S. and Van den Mooter, G. J. Pharm. Pharmacol. 2009, 61, 1571 - 1586). However, there is no general or reliable method for selecting a technology or polymer to ensure amorphous stability and improve bioavailability. It has been reported that solubility parameters assist in polymer selection. However, there is generally no way to predict the benefit of using a specific polymer and / or a specific method for preparing a solid dispersion over another specific polymer and / or specific method in providing a stable amorphous dispersion of a given drug.

[0078] Another unknown factor is the effect of the drug load of a given drug formulation. It has also been found that the drug load in an amorphous solid dispersion is crucial for the stability of any given formulation. Generally, the lower the drug load, the better the stability of the dispersion. Beyond a certain drug load, the risk of recrystallization of the amorphous solid dispersion during shelf-life storage is high, thus reducing the benefit of improved solubility and bioavailability. It can thus be seen that although theoretically, amorphous solid dispersions can improve the bioavailability of a drug substance, it is not an easy task to provide a stable pharmaceutical dosage form of a drug substance in the form of an amorphous solid dispersion.

[0079] Despite these obstacles, the present invention provides an amorphous solid dispersion comprising Compound A (as a free base or as a pharmaceutically acceptable salt thereof) and one or more stabilizing polymers, wherein Compound A can be successfully administered in a bioavailable manner to a patient in need, and wherein the oral dosage form of Compound A is stable.

[0080] The amorphous solid dispersions of the present invention can be formed by any conventional technique, such as spray drying, co-grinding, hot melt extrusion, freeze drying, rotary evaporation, solvent evaporation, co-precipitation, lyophilization, or any suitable solvent removal method.

[0081] Without wishing to be bound by theory, the stabilizing polymers in the solid dispersion can reduce the molecular mobility of the drug to avoid phase separation and recrystallization of the drug during storage. However, it should be recognized that the presence of certain foreign excipients may compromise the stability of the solid dispersion (e.g., remaining amorphous). It has been found that the choice of polymers and methods for amorphous solid dispersions plays a key role in the solubility and stability of the solid dispersion. However, there is no absolute a priori method to determine whether a given polymer or method will provide sufficient solubility and stability for an amorphous solid dispersion.

[0082] In one embodiment, the amorphous solid dispersion of the present application comprises Compound A and one or more stabilizing polymers, wherein the one or more stabilizing polymers are selected from polyvinylpyrrolidone (povidone or PVP), crospovidone (crosslinked polyvinylpyrrolidone or PVP-XL), hydroxypropylcellulose (HPC), low-substituted hydroxypropylcellulose (L-HPC), hypromellose (HPMC), hypromellose acetate succinate (HPMC-AS), hypromellose phthalate (HPMC-P), carboxymethylcellulose, croscarmellose sodium (NaCMC), methylcellulose, hydroxyethylcellulose, carboxyethylcellulose, carboxymethylcellulose, carboxymethylhydroxyethylcellulose, polyethylene glycol (PEG), polyvinyl alcohol, polyvinylpyrrolidone-vinyl acetate copolymer (copovidone or PVP / VA), polyethylene glycol-polyvinyl alcohol copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyacrylate, polymethacrylate, or mixtures thereof.

[0083] In one embodiment, the amorphous solid dispersion of the present application comprises Compound A and one or more stabilizing polymers, wherein the one or more stabilizing polymers are polyvinylpyrrolidone (PVP). Various specific molecular grades of PVP can be used; for example, poly(vinylpyrrolidone-co-vinyl acetate 60:40 (PVP VA64) or PVP K30.

[0084] In one embodiment, the amorphous solid dispersion of the present application comprises Compound A and one or more stabilizing polymers, wherein the one or more stabilizing polymers are polyvinylpolypyrrolidone (cross-linked povidone or PVP XL).

[0085] In one embodiment, the amorphous solid dispersion of the present application comprises Compound A and one or more stabilizing polymers, wherein the one or more stabilizing polymers are sodium carboxymethylcellulose (NaCMC) or low-substituted hydroxypropyl cellulose (L-HPC).

[0086] In one embodiment, the amorphous solid dispersion of the present application comprises Compound A and one or more stabilizing polymers, wherein the one or more stabilizing polymers are polymethacrylates, preferably L100 or L100-55.

[0087] is a brand name for a series of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic acid / acrylates or their derivatives. L100 is an anionic copolymer of methacrylic acid and methyl methacrylate, wherein the ratio of free carboxyl groups to ester groups is about 1:1. L100-55 is an anionic copolymer based on methacrylic acid and ethyl acrylate, wherein the ratio of free carboxyl groups to ester groups is about 1:1.

[0088] In a preferred embodiment, the amorphous solid dispersion of the present application comprises Compound A, one or more stabilizing polymers, wherein the one or more stabilizing polymers are hydroxypropyl methylcellulose (HPMC). Various grades of hydroxypropyl methylcellulose can be used, such as those containing different ratios of hydroxypropyl and methoxy groups. The following types of hydroxypropyl methylcellulose specified in the pharmacopoeias (Ph.Eur., USP / NF, and JP) can be used.

[0089] Table 1: Types of HPMC Specified in Ph.Eur., USP / NF, and JP

[0090] Substitution type Methoxy [%] Hydroxypropoxy [%] HPMC 1828 16.5 to 20.0 23.0 to 32.0 HPMC 2208 19.0 to 24.0 4.0 to 12.0 HPMC 2906 27.0 to 30.0 4.0 to 7.5 HPMC 2910 28.0 to 30.0 7.0 to 12.0

[0091] An example of a stabilizing polymer used in the present invention is HPMC 2910, which has about 29% methoxy groups and about 10% hydroxypropoxy groups. HPMC 2910 is also known as "HPMC 603".

[0092] In one embodiment, the amorphous solid dispersion of the present application comprises Compound A and one or more stabilizing polymers, wherein the one or more stabilizing polymers are hypromellose acetate succinate (HPMC-AS), preferably HPMC-AS-L, HPMC-AS-M or HPMC-AS-H.

[0093] In one embodiment, the amorphous solid dispersion of the present application comprises Compound A and one or more stabilizing polymers, wherein the one or more stabilizing polymers are a mixture of hypromellose (HPMC) and hypromellose acetate succinate (HPMC-AS).

[0094] The amorphous solid dispersion of the present invention may also optionally comprise one or more pharmaceutically acceptable excipients selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, basic stabilizers, colorants, flavorants, preservatives and combinations thereof.

[0095] As used herein, the term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable", i.e., compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without producing excessive toxicity, irritation, allergic responses, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio. Examples of such excipients include, but are not limited to, solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, basic stabilizers, coloring agents, flavoring agents, and preservatives. One of ordinary skill in the art can select one or more of the foregoing excipients by routine experimentation based on the specific desired properties of the solid oral dosage form without undue burden. The amount of each excipient used can vary within the ranges conventional in the art. Techniques and excipients for formulating oral dosage forms are disclosed in the following references, which are hereby incorporated by reference in their entirety. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th Edition; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition; Gibson, ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0096] The amorphous solid dispersions of the present invention may optionally contain one or more lubricants or glidants, i.e., substances or materials that improve the properties (e.g., processability) of the solid dispersion. Lubricants or glidants suitable for the compositions of the present invention include silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose fatty acid esters, microcrystalline wax, yellow beeswax, white beeswax, and the like, and mixtures thereof, preferably silica, more preferably colloidal silica.

[0097] In one embodiment, the amorphous solid dispersion of the present application comprises Compound A, one or more stabilizing polymers, and optionally one or more pharmaceutically acceptable excipients, namely glidants. Specifically, it has been found that when a mixture of a glidant (such as silica), a stabilizing polymer (e.g., HPMC), and Compound A is blended and subjected to a hot melt extrusion process, the resulting extrudate exhibits improved milling properties, a better compressibility profile, and an improved disintegration time of the resulting oral dosage form.

[0098] The amorphous solid dispersion of the present invention may optionally comprise one or more solubilizers, i.e., additives that increase the solubility or dissolution rate of the pharmaceutically active ingredient in the solid dispersion or additives that act as pore formers in the solid dispersion. Solubilizers may be selected from surfactants, nonionic copolymers, bile salts, and hydrotropes. Solubilizers suitable for the compositions of the present invention include, but are not limited to, cyclodextrins, poloxamers, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene sorbitan fatty acid esters (such as polysorbate 80), alkyl sulfates or sulfonates (such as sodium dodecyl sulfate or dioctyl sodium sulfosuccinate), lecithin, D-α-tocopheryl polyethylene glycol succinate, polyethoxylated castor oil (such as RH 40 and EL / ELP), polyoxyethylene stearate, polymethacrylate-based copolymers (such as EPO and L 100-55), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (such as ), polyoxyethylene alkylaryl ethers (such as polyoxyethylene stearyl ether), polyethylene glycol fatty acid esters (such as PEG stearate or PEG hydroxystearate), sodium taurocholate, sodium benzoate, etc. and combinations thereof.

[0099] The amorphous solid dispersion of the present invention may optionally contain one or more surfactants. Surfactants are compounds capable of improving the wettability of drugs and / or enhancing dissolution. Surfactants may be selected from hydrophilic surfactants, lipophilic surfactants, or mixtures thereof. Surfactants may be anionic, non-ionic, cationic, and zwitterionic surfactants. Surfactants according to the present invention may include, but are not limited to, non-ionic copolymers such as poloxamer 188; polyoxyethylene alkyl aryl ethers such as polyoxyethylene dodecyl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate, PEG stearate, PEG hydroxystearate; vitamin E PEG 1000 succinate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid monoesters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate; alkyl sulfates or sulfonates such as sodium dodecyl sulfate, sodium dioctyl sulfosuccinate; lecithin; stearyl alcohol; cetearyl alcohol; cholesterol; polyoxyethylene castor oil; polyoxyethylene glycerol fatty acid esters; RH 40; cremophor EL / ELP, etc. or combinations thereof.

[0100] In some aspects, the drug loading percentage of Compound A in the amorphous solid dispersion is from about 1% to about 90% (w / w) (e.g., from 1% to 5%, from 5% to 10%, from 5% to 20%, from 5% to 30%, from 5% to 40%, from 5% to 50%, from 5% to 60%, from 5% to 70%, from 5% to 80%, from 5% to 90%, from 10% to 20%, from 10% to 30%, from 10% to 40%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 20% to 30%, from 20% to 40%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 21% to 30%, from 21% to 34%, from 21% to 40%, from 21% to 50%, from 21% to 60%, from 21% to 70%, from 21% to 80%, from 21% to 90%, from 30% to 40%, from 30% to 50%, from 30% to 60%, from 30% to 70%, from 30% to 80%, from 30% to 90%, from 36% to 40%, from 36% to 49%, from 36% to 60%, from 36% to 70%, from 36% to 80%, from 36% to 90%, from 40% to 50%, from 40% to 60%, from 40% to 70%, from 40% to 80%, from 40% to 90%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 51% to 60%, from 51% to 70%, from 51% to 80%, from 51% to 90%, from 60% to 70%, from 60% to 80%, from 60% to 90%, from 70% to 80%, and from 70% to 90%). In some preferred embodiments, the percentage loading of Compound A is from about 1% to about 90% (w / w), from about 10% (w / w) to about 85% (w / w), preferably from about 15% (w / w) to about 80% (w / w), from about 20% (w / w) to about 75% (w / w), or from about 30% (w / w) to about 60% (w / w).

[0101] In some aspects, the ratio of the weight of Compound A to the weight of one or more stabilizing polymers in the amorphous solid dispersion of the present invention is from about 5:95 to about 90:10, about 40:60, about 80:20; preferably about 60:40.

[0102] In one aspect, a method of preparing an amorphous solid dispersion as described herein is provided, which includes preparing a mixture (e.g., a solid mixture) of Compound A, one or more stabilizing polymers, and optionally one or more pharmaceutically acceptable excipients (such as glidants), heating the mixture to form a melt; extruding the melt; and cooling the melt to form an amorphous solid dispersion (e.g., hot melt extrusion).

[0103] The resulting amorphous solid dispersion is directly processed into the final dosage form or further processed into the final dosage form. For example, the amorphous solid dispersion can be blended with one or more excipients as described herein after milling, granulating and then compressing to produce a final blend for encapsulation or tableting. In certain embodiments, the solid dispersion can be combined with one or more excipients (such as binders, fillers, disintegrants, wetting agents, glidants and lubricants), and the resulting mixture can be granulated to form granules containing the solid dispersion and one or more excipients.

[0104] Hot melt extrusion method

[0105] In some aspects, the solid dispersions of the present invention can be made by hot melt extrusion (“hot melt extrusion”), for example, a method in which the composition is heated and / or compressed to a molten (or softened) state and then forced through an orifice in a die, and the extruded product forms its final shape therein and solidifies upon cooling. Hot melt extrusion is simple and easy to operate, and reduces energy consumption and increases productivity.

[0106] In the hot melt extrusion method, the blend is typically conveyed through one or more heating zones by a screw mechanism. The screw is rotated by a variable speed motor within a cylindrical barrel, with only a small clearance between the outer diameter of the screw and the inner diameter of the barrel. In this configuration, high shear is generated between the barrel wall and the screw, and the various components of the powder blend are thoroughly mixed and decomposed by this high shear. The die can be a bi-tube, multi-tube or feed block die. As used herein, the term extrudate refers to the composition hot melt extruded.

[0107] In one embodiment, the amorphous solid dispersion of the present application is obtained by hot melt extrusion. A physical mixture of Compound A, one or more stabilizing polymers and optionally one or more pharmaceutically acceptable excipients can be hot melt extruded at about 25°C to about 200°C (e.g., about 25°C to about 170°C) using a hot melt extruder with a twin screw (such as a Thermo Fisher Pharma 11mm twin screw or a Leistritz ZSE18mm HPe-PH twin screw). The resulting hot melt extruded product can be cooled, milled and passed through a 0.5mm sieve.

[0108] In other embodiments, the mixture can be fed into a hot melt extruder having a temperature zone of about 25°C to about 200°C (e.g., about 25°C to about 170°C) to produce an extrudate.

[0109] Preferably, hot melt extrusion is carried out at a temperature that allows the melting of Compound A and one or more stabilizing polymers. In certain embodiments, the mixture of Compound A and one or more stabilizing polymers can be heated to near or above the glass transition temperature T g or the melting temperature T m to form a liquid mixture. After the mixture is heated to form a melt, it can be extruded and cooled to form a solid dispersion.

[0110] The temperature and screw speed of the hot melt extruder can be selected based on the type of pharmaceutically acceptable carrier employed, e.g., to smoothly extrude the target mixture, where the extrusion speed and yield meet the required requirements and the desired amorphization and dispersion effects.

[0111] In certain aspects, optionally, the mixture of Compound A and one or more stabilizing polymers may further comprise a glidant to enhance the grinding properties, compressibility profile, and improve the disintegration time of the extrudate. Exemplary glidants include silica in any useful or effective amount of the amorphous solid dispersion (e.g., about 1% to about 10% (w / w), e.g., about 3% (w / w)).

[0112] The extrudate can optionally be granulated or milled to form a solid dispersion suitable for further processing into a suitable unit dosage form. In certain aspects, the extrudate is subsequently granulated and milled to produce granules of the extrudate. The milled / granulated extrudate can be used for encapsulation or tableting. In a particular embodiment, the milled / granulated extrudate forms an inner phase (e.g., the granule component), which can be sieved and blended with various pharmaceutically acceptable excipients (such as binders, fillers, disintegrants, wetting agents, glidants, and lubricants) that form an outer phase (e.g., the outer granule component), where the resulting blend is used for encapsulation or tableting.

[0113] Pharmaceutical composition

[0114] The amorphous solid dispersion of the present invention can be used to fill any of the unit dosage forms (e.g., capsules) described herein or for tableting.

[0115] The solid dispersion can optionally be further processed before filling or tableting. Exemplary further processing includes spheronization, granulation, milling, injection molding, sieving, and / or calendering of the solid dispersion.

[0116] The amorphous solid dispersion of the present invention can optionally be subjected to a particle size reduction procedure before or after the product drying or cooling is completed to produce the desired particle size and particle size distribution. Milling or micronization can be carried out to achieve the desired particle size or distribution. Equipment that can be used for particle size reduction includes, but is not limited to, ball mills, roller mills, hammer mills, pin mills, and jet mills. Preferably, the amorphous solid dispersion of the present invention is milled to form particles.

[0117] The particles of the amorphous solid dispersion of the present invention can be combined with one or more pharmaceutically acceptable excipients to form other pharmaceutical compositions or finished dosage forms. The one or more additional pharmaceutically acceptable excipients can be selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, basic stabilizers, colorants, flavorants, preservatives, and combinations thereof.

[0118] In one embodiment, the pharmaceutical composition of the present invention comprises an amorphous solid dispersion and optionally one or more pharmaceutically acceptable excipients selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, basic stabilizers, colorants, flavorants, preservatives, and combinations thereof.

[0119] The pharmaceutical composition of the present invention can be in the form of an oral dosage form, such as tablets, capsules, cachets, beads, granules, oral suspensions, oral solutions, or microemulsions, preferably tablets.

[0120] The tablets or granules of the present invention can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, the tablets can be coated with a suitable polymer or conventional coating material to achieve, for example, greater stability in the gastrointestinal tract or a desired release rate. For example, the tablets can be coated with hydroxypropyl methylcellulose (HPMC), magnesium stearate, polyethylene glycol (PEG), polyvinyl alcohol (PVA), Opadry or a mixture thereof. For example, a delayed-release material, such as glyceryl monostearate or glyceryl distearate, can be employed. Tablets of any shape or size can be prepared, and they can be opaque, colored, or flavored. In particular, the pharmaceutical composition as disclosed herein is in the form of film-coated tablets.

[0121] In one embodiment, the pharmaceutical composition of the present invention comprises particles of an amorphous solid dispersion of Compound A, which are optionally mixed with one or more additional pharmaceutically acceptable excipients (e.g., extragranular materials) and compressed into tablets or filled into hard gelatin capsules.

[0122] In one embodiment, the pharmaceutical composition of the present invention is in the form of a tablet or a capsule, which comprises: (a) an amorphous solid dispersion of Compound A in the form of particles, (b) at least one intragranular excipient, (c) at least one extragranular excipient, and (d) optionally, a coating.

[0123] The particulate excipients may be selected from one or more or all of the following: (i) diluents, (ii) disintegrants; (iii) lubricants and (iv) glidants.

[0124] The diluent may be present in an amount of about 10% to about 60% weight / weight (w / w) of the total composition.

[0125] The disintegrant may be present in an amount of about 1% to about 10% weight / weight (w / w) of the total composition.

[0126] The lubricant may be present in an amount of about 1% to about 2% weight / weight (w / w) of the total composition.

[0127] The glidant may be present in an amount of about 1% to about 3% weight / weight (w / w) of the total composition.

[0128] The particulate excipients may also be selected from one or more or all of the following: (i) diluents such as microcrystalline cellulose, lactose or combinations thereof; (ii) disintegrants such as crospovidone, croscarmellose sodium or combinations thereof; (iii) lubricants (e.g., sodium stearyl fumarate) and (iv) glidants such as silica.

[0129] The particulate excipients may be selected from one or more or all of the following: (i) 10 - 60% diluent such as microcrystalline cellulose, lactose or combinations thereof; (ii) 1 - 10% disintegrant such as crospovidone, croscarmellose sodium or combinations thereof; (iii) 1 - 2% lubricant (e.g., sodium stearyl fumarate) and (iv) 1 - 3% glidant such as silica, where % refers to % weight / weight (w / w) of the total composition.

[0130] The present invention provides a pharmaceutical composition comprising particles of the amorphous solid dispersion as described herein and a particulate outer phase.

[0131] The pharmaceutical composition of the present invention may comprise one or more lubricants or glidants. In one embodiment, suitable lubricants or glidants include silica, stearic acid, magnesium stearate, sodium stearyl fumarate, calcium stearate, talc, hydrogenated castor oil, sucrose fatty acid esters, microcrystalline wax, yellow beeswax, white beeswax, etc. and mixtures thereof.

[0132] In one embodiment, the glidant is included in the inner particulate material or the outer particulate material or both. Preferably, the glidant is silica, more preferably colloidal silica.

[0133] In one embodiment, the concentration range of the glidant is about 1% to about 3% w / w of the total composition.

[0134] In one embodiment, the concentration of the lubricant ranges from about 1% to about 2% w / w of the total composition. Preferably, the lubricant is magnesium stearate.

[0135] The pharmaceutical composition of the present invention may comprise one or more disintegrants (e.g., substances or materials added to an oral solid dosage form (e.g., a tablet) that assist in its disintegration by causing rapid rupture of the solid dosage form upon contact with moisture).

[0136] In one embodiment, suitable disintegrants include sodium croscarmellose, low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpolypyrrolidone (cross-linked povidone), sodium bicarbonate, sodium starch glycolate, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, etc. and mixtures thereof, preferably sodium bicarbonate and cross-linked povidone, more preferably sodium croscarmellose.

[0137] In one embodiment, the concentration of the disintegrant ranges from about 1% to about 10% w / w of the total composition.

[0138] The pharmaceutical composition of the present invention may comprise one or more fillers. In one embodiment, suitable fillers include microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tricalcium phosphate, calcium sulfate, powdered cellulose, glucose binder, dextrin, glucose excipient, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, refined superfine sugar, etc. and mixtures thereof.

[0139] In one embodiment, the concentration of the filler ranges from about 15% to about 60% w / w of the total composition, preferably about 10% to about 40%, more preferably about 37% w / w.

[0140] The pharmaceutical composition of the present invention may comprise one or more diluents. In one embodiment, suitable diluents include microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tricalcium phosphate, calcium sulfate, powdered cellulose, glucose binder, dextrin, glucose excipient, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, refined superfine sugar, etc. and mixtures thereof, preferably lactose, microcrystalline cellulose or a mixture of lactose and microcrystalline cellulose.

[0141] In one embodiment, the concentration of the diluent ranges from about 15% to about 60% w / w of the total composition, preferably about 10% to about 40%, more preferably about 37% w / w.

[0142] Dosage and Administration

[0143] The pharmaceutical compositions described herein can be used in a method of treatment, wherein an effective amount of Compound A is administered to a patient. The pharmaceutical compositions described herein can be used to treat cancer, particularly cancers having alterations in the MAPK pathway, such as KRAS mutant NSCLC (non-small cell lung cancer), KRAS mutant pancreatic cancer (e.g., KRAS mutant pancreatic ductal adenocarcinoma (PDAC)), KRAS mutant CRC (colorectal cancer), and NRAS mutant melanoma.

[0144] For administration to an animal or human subject, the pharmaceutical composition contains an effective dose of Compound A. Formulations can be prepared using conventional methods, e.g., depending on the subject to be treated, the mode of administration, and the type of treatment desired (e.g., prophylaxis, prevention, or treatment).

[0145] Compound A can be present in an amount of from 1 to 90% by weight, based on the total weight of the composition.

[0146] Preferably, the pharmaceutical composition will be provided in a dosage form suitable for oral administration, including but not limited to hard capsules (e.g., hard gelatin capsules or hard hydroxypropyl methylcellulose capsules), soft gelatin capsules, tablets, cachets, enteric-coated tablets, chewable tablets, enteric-coated hard gelatin capsules, enteric-coated soft gelatin capsules, microcapsules, lozenges, films, strips, gelcaps, dragees, suspensions, syrups, or powders. The composition can be formulated according to conventional pharmaceutical practice.

[0147] The dosage level can depend on the nature of the condition, the efficacy of the drug, the condition of the patient, the judgment of the practicing physician, and the frequency and mode of administration. Unit dosage forms can be administered to achieve any of the daily dosages described herein, such as one to four times daily (e.g., once, twice, three times, or four times daily).

[0148] In one aspect, the invention provides a pharmaceutical composition in unit dosage form for oral administration, the composition comprising from about 10 mg to about 1200 mg (e.g., about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg) of Compound A. Preferred doses include 50 mg, 100 mg, 200 mg, or 300 mg of Compound A.

[0149] The term "unit dosage form" refers to physically discrete units suitable as unit doses, such as tablets, cachets, hard capsules, or soft capsules, each unit containing a predetermined quantity of the drug.

[0150] An "effective" amount refers to an amount of a drug sufficient to treat, prevent, or improve the condition of a subject or patient. The effective amount of Compound A for practicing the present invention to treat a condition can be determined and adjusted by one of ordinary skill in the art to provide an appropriate amount and dosage regimen, for example, depending on one or more of the mode of administration, the age, weight, sex, and / or general health of the patient.

[0151] The term "treat" any disease or disorder means to improve the disease or disorder (e.g., slow, arrest, or reduce the development of the disease, or at least one of its clinical symptoms). In addition, the term also refers to alleviating or improving at least one physical parameter, including parameters that a patient may not be able to discern, and modulating the disease or disorder, whether physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both.

[0152] The term "prevent" or "prevention" of any disease or disorder means delaying the onset, development, or progression of the disease or disorder.

[0153] As used herein, the term "about" is intended to provide flexibility to the endpoints of a numerical range by providing that a given value can be "slightly higher" or "slightly lower" than the endpoint, to account for variations that may be seen in measurements made between different instruments, samples, and sample preparations. The term generally means within 10% of a given value or range, preferably within 5%, more preferably within 1%.

[0154] The terms "pharmaceutical composition" or "formulation" are used interchangeably herein and refer to a physical mixture containing a therapeutic compound to be administered to a mammal (e.g., a human) in order to prevent, treat, or control a specific disease or condition affecting the mammal. These terms also include, for example, intimate physical mixtures formed under high temperature and pressure.

[0155] The term "oral administration" represents any method of administration in which the therapeutic compound can be administered via the oral route by swallowing, chewing, or sucking an oral dosage form. Such oral dosage forms are traditionally designed to effect sufficient release and / or delivery of the active agent in the gastrointestinal tract outside the mouth and / or in the mouth.

[0156] As used herein, the term "therapeutically effective amount" of a compound refers to an amount capable of eliciting a biological or medical response in a subject, e.g., improving symptoms, alleviating a condition, slowing or delaying disease progression, etc. The term "therapeutically effective amount" also refers to an amount of a compound that is effective in at least partially alleviating and / or improving a condition, disorder, or disease when administered to a subject. The term "effective amount" refers to the amount of the subject compound that elicits a biological or medical response sought by a researcher, physician, or other clinician in a cell, tissue, organ, system, animal, or human.

[0157] Unless otherwise specified, the term "comprising" as used herein is used in its open-ended and non-limiting sense. In more limited embodiments, "comprising" may be replaced with "consisting of", which is no longer open-ended. In the most limited version, it may only include the characteristic steps or the values listed in the corresponding embodiment.

[0158] Abbreviations

[0159] % w / w Weight / weight percentage

[0160] °C Degrees Celsius

[0161] API Active pharmaceutical ingredient

[0162] API-NXB (or NXB) Compound A in the form of monohydrate H A Compound A in form

[0163] API-NXA (or NXA) Compound A in anhydrous form A

[0164] API-GR (from Figure 2 ) Particles containing Compound A

[0165] ASD Amorphous solid dispersion

[0166] AUC Area under the curve

[0167] AUCinf AUC curve up to infinite time

[0168] AUClast AUC up to the last measurable concentration

[0169] Cmax Maximum concentration

[0170] Cellulose HP-M 603 Hydroxypropyl methylcellulose

[0171] Cellulose MK GR Microcrystalline cellulose (MCC) particles

[0172] CV% Coefficient of variation (%)

[0173] CSF Clinical service form (formulation)

[0174] DR Dissolution rate

[0175] DSC Differential scanning calorimetry

[0176] FaSSIF Fasted-state simulated intestinal fluid

[0177] FCT Film-coated tablets

[0178] FeSSIF Fed-state simulated intestinal fluid

[0179] g / min grams per minute

[0180] HME Hot Melt Extrusion

[0181] HPLC High Performance Liquid Chromatography

[0182] HR-XRPD High Resolution X-ray Powder Diffraction

[0183] INCI International Nomenclature of Cosmetic Ingredients

[0184] INN International Nonproprietary Name

[0185] IPC In-Process Control

[0186] Kg / g / mg / ng / μg Kilogram / gram / milligram / nanogram / microgram

[0187] kN Kilonewton

[0188] LCMS Liquid Chromatography-Mass Spectrometry

[0189] Lactose SD (or Figure 2 spray-dried lactose in

[0190] sugar gesprueht)

[0191] LOD Loss on Drying

[0192] MEPC Microemulsion Preconcentrate

[0193] MG / G Milligram / gram

[0194] mL / L Milliliter / liter

[0195] MRT Mean Residence Time

[0196] Na-CMC-XL Sodium Carboxymethylcellulose

[0197] nm / μm Nanometer / micrometer

[0198] PCS Photon Correlation Spectroscopy

[0199] Ph.Eur. European Pharmacopoeia

[0200] PK Pharmacokinetics

[0201] PSASD Polymer-Stabilized Amorphous Solid Dispersion

[0202] PSD Particle Size Distribution

[0203] RH Relative Humidity

[0204] Rpm Revolutions Per Minute

[0205] RRT Relative retention time

[0206] RT Room temperature

[0207] SD and RSD Standard deviation and relative standard deviation

[0208] SEM Scanning electron microscope

[0209] SLS Sodium lauryl sulfate

[0210] TFA Trifluoroacetic acid

[0211] TGA Thermogravimetric analysis

[0212] Tmax Time to reach the maximum concentration (Cmax)

[0213] US Ultrasonic treatment

[0214] USP United States Pharmacopeia

[0215] USP / NF United States Pharmacopeia / National Formulary

[0216] w / v Weight / volume

[0217] w / w Weight / weight

[0218] XRPD X-ray powder diffraction

[0219] Example

[0220] The following examples illustrate the invention and provide support for the disclosure of the invention, but do not limit the scope of the invention.

[0221] Example 1: Properties of various physical forms of Compound A

[0222] Several physical forms of Compound A were analyzed: free base, tartrate, and tosylate. A summary of the properties of these physical forms is provided in Table 1A.

[0223] Table 1A

[0224]

[0225] The tartrate form was found to be the most unstable compound among the three forms and was hygroscopic. The free base was found to have comparable stability and hygroscopicity to the tosylate. However, the free base had at least two polymorphic forms, while no polymorphic issues were observed for the tosylate. The solubility of the tosylate in aqueous media was not significantly improved, and there may be potential toxicity risks during processing. The different physical forms of Compound A described above showed similar poor solubility.

[0226] Compound A has very limited solubility at all pH values. Table 1B provides the solubilities of the amorphous free base, crystalline hydrate, and crystalline tosylate forms of Compound A. Table 1B shows some pH-dependent solubility profiles, but even at low pH, the solubility of Compound A is limited.

[0227] Table 1B

[0228]

[0229] Table 1C provides the photostability of the crystalline hydrate and crystalline tosylate forms of Compound A under light or photo-stress. Table 1C shows that the crystalline hydrate and crystalline tosylate forms of Compound A are stable as bulk solids under photo-stress, but are prone to degradation under photo-stress in solution form. Table 1D shows that the crystalline tosylate form of Compound A is stable as a bulk solid for 5 days under thermal stress at room temperature (RT), 50 °C, and 80 °C. Table 1E shows that the crystalline tosylate form of Compound A is prone to degradation in solution / suspension under heat at low pH values.

[0230] Table 1C

[0231]

[0232] Table 1D

[0233]

[0234] Table 1E

[0235]

[0236] Therefore, from the above, it can be seen that it is not easy to select which specific form of Compound A to process into an oral dosage form suitable for administration to patients in need.

[0237] Example 2: Pharmacokinetics of Compositions of Salt and Free Base Forms of Compound A

[0238] As summarized in Tables 2A and 2B, the pharmacokinetics of Compound A were studied in dogs following a single oral dose of 100 mg / kg of Compound A (as tosylate in a suspension with surfactant, free base in a suspension with surfactant, and free base in a microemulsion). For each phase, the dogs were fasted overnight from normal feeding until approximately 4 hours after dosing. Each dog was dosed orally via gavage at 100 mg / kg (4 mL / kg), and then flushed with 10 mL of water. The concentration of Compound A in plasma samples was quantified by liquid chromatography-tandem mass spectrometry.

[0239] Table 2A

[0240]

[0241] Table 2B

[0242] Preparation Group 1 Group 2 Group 3 PK parameter Mean ± SD Mean ± SD Mean ± SD Tmax (h) 1.7±0.58 17±13 1.7±0.58 Cmax (ng / mL) 3290±961 275±148 7680±839 AUC0-24h (h.ng / mL) 48200±20000 4370±1900 93700±28700 AUC0-48h (h.ng / mL) 67000±26900 8640±4720 123000±46300 AUClast (h.ng / mL) 72900±31400 9410±5240 133000±53400 T1 / 2 (h) 14±5.0 23±14 14±4.2 AUCinf (h.ng / mL) 76000±34500 12200±6530 138000±56600 AUCinf / dose ((h.ng / mL) / (mg / kg)) 760±345 122±65.3 1380±566

[0243] Overall, the free base in the microemulsion produced the highest AUC0-24h (93700 h·ng / mL) in dogs, followed by the tosylate in the suspension (where AUC0-24h = 48200 h·ng / mL) and the free base in the suspension (where AUC0-24h = 4370 h·ng / mL). However, the composition in Study Group 3 was found to be a relatively unstable microemulsion.

[0244] Example 3: Pharmacokinetics of Compound A in Various Formulations

[0245] As summarized in Tables 3A and 3B, the pharmacokinetics of Compound A were studied in dogs following a single oral dose of 30 mg / kg of Compound A (as the tosylate in a polymer-rich suspension (Stages A, B, C), as an amorphous solid dispersion tablet of the free base (Stage D), and as a free base microemulsion (Stage E)).

[0246] Preparation of the Administered Formulations

[0247] For Stages A - C, an appropriate amount of the test drug substance, i.e., crystalline tosylate of Compound A, was weighed into a suitable container. Each formulation was prepared separately for each dog in a separate container as follows: 30 mg / kg dose (40.3 mg / kg tosylate) was weighed and 0.2 M Na 2 HPO 4 and a vehicle of 0.1 M aqueous citric acid (3 mL / kg) were added. Separately, in Stage A the vehicle was enriched with 1% (w / v) EPO, in Stage B 1% (w / v) hydroxypropyl cellulose (HPC), and in Stage C 1% (w / v) RH40. The resulting suspensions were stored at ambient temperature (18 - 30 °C) and administered within 15 - 30 minutes after formulation preparation. For Stage D, an amorphous solid dispersion tablet containing 300 mg of Compound A was prepared according to Example 10.

[0248] For Phase E, prepare an active microemulsion preconcentrate (MEPC) of Compound A at 100 mg / mL (composition of the inactivated MEPC: ethanol, PEG400, Maisine CC, Kolliphor RH40). Prepare the formulation for each dog individually in a separate container as follows: Measure 0.3 mL / kg of Compound A MEPC to 0.7 mL / kg of water to produce a microemulsion. The corresponding concentration is 30 mg / mL of Compound A, a dose of 30 mg / kg. Store the formulation at ambient temperature (18 - 30 °C) and administer within 15 - 30 minutes after preparation.

[0249] For each phase, fast the dogs overnight from normal feeding until approximately 4 hours after dosing. For Phases A, B, and C, administer the suspension formulation (3 mL / kg) to six conscious dogs by oral gavage, then flush the gavage line with 2 mL / kg of water, for a total volume of 5 mL / kg. For Phase D, administer one tablet orally to each dog, then administer the pH 2.6 buffer by oral gavage at 3 mL / kg and flush the gavage line with 2 mL / kg of water, for a total volume of 5 mL / kg. During Phase E, administer the microemulsion (1 mL / kg) to six conscious dogs by oral gavage, then administer the pH 2.6 buffer by oral gavage at 3 mL / kg and flush the gavage line with 1 mL / kg of water, for a total volume of 5 mL / kg.

[0250] Table 3A

[0251]

[0252] Table 3B

[0253]

[0254] After oral dose administration, collect blood samples continuously until 96 h after administration. After collection, centrifuge each sample to produce plasma and analyze all plasma samples using a suitable LC-MS / MS assay with a lower limit of quantification (LLOQ) of 1.0 ng / mL for Compound A.

[0255] Comparing AUClast / dose, the exposure (AUClast / D 476 ± 266) after administration of formulation D (amorphous solid dispersion formulation) by tablet was significantly higher than that after oral gavage administration of formulation A (Eudragit formulation) (AUClast / D 68.3 ± 39.8), oral gavage administration of formulation C (AUClast / D 140 ± 29.4), and oral gavage administration of formulation B (HPC formulation) (AUClast / D 167 ± 30.0), and was significantly lower than that after oral gavage administration of formulation E (MEPC formulation) (AUClast / D 2250 ± 119). However, the microemulsion was observed to be relatively unstable. In addition, due to the need to ingest a large amount of lipid vehicle for each administration, the MEPC formulation may not be suitable for treatment.

[0256] Example 4: Pharmacokinetics of Compound A in ASD Formulations.

[0257] The evaluation of the amorphous solid dispersion (ASD) formulations of Compound A was as follows. As summarized in Tables 4A and 4B, in a crossover study in dogs, using a nominal dose of 60 mg / kg, the pharmacokinetics of hot melt extrusion (HME) solid dispersions and spray dried (SD) solid dispersions as suspensions were evaluated and compared with a micronized Compound A (API) suspension (as a reference). Hydroxypropyl methylcellulose (HPMC / hydroxypropylmethylcellulose) is the stabilizing polymer used in the hot melt extrusion ASD. Copovidone (PVP VA64) and EPO are the stabilizing polymers used in the spray dried ASD.

[0258] Dogs were fasted overnight from normal feeding until 4 hours after dosing. Each dog was acclimated by oral gavage with 2 mL / kg phosphate-citrate buffer pH 2.6 and the gavage line was rinsed with 5 mL. Subsequently, each formulation was immediately administered by oral gavage with 5 mL / kg of each suspension, and rinsed with 5 mL of water to ensure that there was no formulation left in the gavage tube.

[0259] Table 4A

[0260]

[0261] Table 4B

[0262]

[0263] The bioavailability of hot-melt extrusion and spray-dried solid dispersion formulations was found to be up to 3.7-fold and 2.2-fold higher, respectively, compared to micronized API formulations. The hot-melt extrusion and spray-dried amorphous solid dispersion formulations were comparable and had no excipient-related safety issues. Improved pharmacokinetic properties were observed with HPMC-based hot-melt extrusion formulations. The spray-dried amorphous solid dispersion formulations were found to be less stable and were not amenable to roller compaction for densification or compression into tablets.

[0264] Example 5: Clinical Service Formulation of Compound A

[0265] Drug-polymer mixtures of various compositions were prepared by hot-melt extrusion (HME) in a microextruder and their amorphous stability and compatibility with excipients were evaluated, such as as described in Example 8.

[0266] Among the polymers evaluated, the 30% drug-loaded ASD based on hypromellose (e.g., HPMC 2910) and copovidone was identified as the most suitable, especially in terms of amorphous stability and compatibility with excipients. The ASD with these polymers was found to be amorphous by XRPD and maintained physical and chemical stability after short-term storage (1 - 2 weeks) and could be further developed into tablets of 50 mg strength. The HPMC-based tablets showed a faster dissolution rate and greater recovery compared to copovidone-based tablets, and supersaturation persisted for up to 2 hours.

[0267] The clinical service formulation (CSF-1) was available in tablet form at 50 mg (550 mg tablet) and 100 mg (1100 mg tablet) strengths, with a dosage proportion composition containing 9.1% Compound A, 21% hypromellose 2910, 55.6% microcrystalline cellulose, 10% crospovidone, 3.3% colloidal silicon dioxide, and 1% magnesium stearate and could be developed for further stability studies according to International Council for Harmonization (ICH) guidelines and supporting shelf-life.

[0268] Example 6: Animal Studies to Optimize the Amorphous Solid Dispersion Composition of Compound A

[0269] Three animal studies were conducted to understand in detail the in vivo behavior of an amorphous solid dispersion (ASD) composition containing compound A (API). In dog study 1, four different compositions with drug loadings between 30 - 60% were administered to fasted dogs at a dose of 30 mg / kg or 10 mg / kg. The dogs were pretreated with phosphate - citrate buffer pH 2.6, and the compositions were dispersed in water and administered. In dog study 2, three different compositions with a drug loading of 60% were administered to fasted dogs at a dose of 30 mg / kg. The dogs were pretreated with pentagastrin, and the compositions were dispersed in water and administered. In dog study 3, four different compositions were administered to fasted dogs. Formulations C1, C2, and C3 were dispersed in water and administered at 10 mg / kg. Formulation C4 was administered as a whole tablet. After administration, phosphate - citrate buffer pH 2.6 was given to the dogs by oral gavage. Table 6 provides a summary of the pharmacokinetic data for the dog studies.

[0270] Table 6

[0271]

[0272]

[0273] In all studies, the inter - animal variability for all formulations was medium to high. The AUClast and Cmax (mean) of API in plasma were comparable across all treatment groups in each study. However, significant differences were observed between the studies. For example, the pretreatment of dogs before dosing (to normalize gastric pH) had a significant effect on exposure and plasma concentration. In study 2, the dogs were pretreated with 6 μg / kg pentagastrin, and in studies 1 and 3, 2 ml / kg of phosphate citrate buffer (pH 2.6) was given before dose administration.

[0274] Based on these studies, it was found that an HPMC - based amorphous solid dispersion composition with a drug loading of 60% had optimal properties.

[0275] Example 7: Influence of Drug Substance Characteristics on Drug Product Properties

[0276] Mixtures of a polymer such as hypromellose (HPMC) and compound A in various physical forms (e.g., in the anhydrous form (referred to herein as "compound A - NXA") and in the monohydrate form (referred to herein as compound A - NXB)) were prepared as separate mixtures and processed into amorphous solid drug dispersions using hot - melt extrusion. A The bulk density of the premix containing the anhydrous form of compound A was 0.07 - 0.11 g / cm

[0277] ​3 , the flow function is 1.5 - 1.8. It is very viscous and difficult to maintain uniform feeding into the extruder. The monohydrate form H of compound A A of the premix has a higher and more favorable bulk density of 0.33 g / cm 3 , the flow function is 2.2 - 2.3, and it can be uniformly fed into the extruder. As Figure 1A and 1B shown, the anhydrous form of compound A has a very fine needle-like crystal structure, while the variant H of compound A A has a more cubic particle morphology.

[0278] Therefore, it can be seen that the amorphous solid dispersion prepared from the variant H of compound A A provides the best flow of the premix during processing (e.g., in the hot melt extrusion method of the present invention).

[0279] Therefore, the present invention provides the use of a crystalline form of compound A (which is not a fine needle-like shape) for a method of preparing an amorphous solid dispersion comprising compound A.

[0280] Example 8: Optimization of the tablet formulation containing compound A

[0281] The optimization of the tablet formulation according to the present invention can be carried out as follows.

[0282] Specifically, it was found that some tablets obtained using an amorphous solid dispersion prepared from compound A in the anhydrous form and hypromellose had some physical defects. In some cases, such tablets showed fine cracks on their sidewalls after overnight storage. Such tablets were also difficult to film coat because sometimes the tablet content of the blend was non-uniform and the disintegration was fast (5 - 10 seconds). In addition, the tablets obtained using an amorphous solid dispersion prepared from compound A in the anhydrous form and hypromellose could only accommodate a low drug load, resulting in large tablets that were difficult to swallow. This led to an excessive burden on patients when taking the medicine, especially when the recommended dose was high, and led to insufficient patient compliance. For example, the total weight of a tablet containing only 9.1% compound A as the drug load (100 mg compound A) was 1100 mg, and the tablet size of the tablet obtained from the ASD prepared from the anhydrous form of compound A was large (20 x 10.6 mm).

[0283] Surprisingly, by using the monohydrate H of compound A ATo prepare amorphous solid dispersions, the drug loading in the amorphous solid dispersions can be significantly increased. Thus, the drug loading in the amorphous solid dispersion containing Compound A can be doubled (from about 30% to 60%). Compared with 100 mg tablets (20x10.6 mm) obtained using amorphous solid dispersions of Compound A in the anhydrous form, the tablet size of 200 mg tablets (17x6.7 mm) can be significantly reduced (by up to 70%). Tablets made from amorphous solid dispersions prepared from Compound A in the monohydrate H A form also have sufficient physical strength to apply a film coating.

[0284] Amorphous solid dispersions prepared with the monohydrate H A form of Compound A and various polymers (HPMC 2910, HPMC-AS-L, HPMC-AS-H, L100-55) were melt-extruded and ground into powders at three different drug loadings (40%, 60%, and 80%) and tested for stability and dissolution rate.

[0285] The two most promising PSASD powders (60% API / 40% HPMC 2910 and 60% API / 30% HPMC-AS-L / 10% HPMC 2910) were further developed into tablets to evaluate their sufficient compressibility / processability, rapid to medium disintegration times, compatibility with excipients, and suitability for film coating. A unit dose range varying from 50 to 300 mg was studied for the two variants. The HPMC variant was selected based on its improved chemical stability and compatibility.

[0286] Film-coated tablets (e.g., 50 and 200 mg strength tablets) can be developed and coated with Opadry II.

[0287] The FMI tablet formulation addresses several drawbacks found in the CSF-2 tablet formulation, mainly related to processability, compressibility, and in vitro performance (disintegration time / dissolution rate). Silica was added to the extrudate together with HPMC and allowed to obtain better extrudate grinding properties, a better compressibility profile, and an improvement in disintegration time. In addition, microcrystalline cellulose was added to the outer phase of the final blend. These improvements provided a more suitable extrudate particle size distribution and overall improved tablet compressibility. In addition, sodium bicarbonate and cross-linked povidone in the CSF-2 tablets were replaced with sodium croscarmellose to facilitate tablet disintegration.

[0288] Table 8 provides the composition of 100 mg CSF1, 200 mg CSF2, and 200 mg FMI tablets. The method for manufacturing the pharmaceutical product involves unit operations of pre - mixing the drug and polymer, hot - melt extrusion, granulation, and milling to obtain a powdered amorphous solid dispersion (ASD). Then, final blending with excipients and lubricants, tablet compression, and film coating are carried out. The tablets, developed as a solid dosage form, do not require special packaging or devices.

[0289] Table 8

[0290]

[0291] Used in CSF1 a in the form of NXA (anhydrous form A), while NXB (monohydrate HA) is used in CSF2 and FMI. b The dose of 100 mg FMI is proportional to the 200 mg composition

[0292] Example 9: FCT composition of Compound A

[0293] Figure 2 Illustrates a representative process flow diagram for manufacturing granules of 600 mg / g Compound A (API) and adding extra - granular components to manufacture film - coated tablets (FCT) of Compound A (API).

[0294] Figure 2 In it, HPM 603 refers to “HPMC 603”, which is also known as HPMC 2910.

[0295] Granules containing 60 wt% Compound A can be prepared according to Table 9A, where wt% refers to the weight of A to the total weight of the granules.

[0296] Hot - melt extrusion is carried out using a Leistritz 18 mm twin - screw extruder with a batch size of 25 kg of the premix. The conditions for hot - melt extrusion are provided in Table 9B.

[0297] Table 9A

[0298]

[0299] Table 9B

[0300]

[0301] After extrusion, the extrudate is milled using a Frewitt hammer mill (hammer forward). The milled extrudate is tested for particle determination, bulk / tap density, particle size distribution (PSD), loss on drying (LOD), differential scanning calorimetry (DSC), and X - ray powder diffraction (XRPD) according to acceptance criteria.

[0302] A total of 10 kg of milled extrudate was used to prepare the final blend. For compression, a total amount of 17.69 kg was available and divided into compression at dose strengths of 50 mg (6 kg final blend = 40,000 units) and 300 mg (11.5 kg final blend = 12,777 units). Tablets were compressed on a rotary press (Fette 1200i) equipped with 8 punches.

[0303] Example 10: Intermediate in the manufacturing method - Granules of Compound A

[0304] Figure 2 The figure illustrates a representative process flow diagram for manufacturing granules of 600 mg / g Compound A (API) and adding extra-granular components to manufacture film-coated tablets (FCT) of Compound A (API).

[0305] The batch formulation in Table 10A represents 1 kg of granules of Compound A (API GR). Table 10B provides the method conditions for hot melt extrusion. The batch size of the granules (used as intermediates) will depend on clinical requirements and / or available starting materials. The weights of the individual components are proportional to the composition.

[0306] Table 10A

[0307]

[0308] *Based on the adjusted amount of drug content in Example 9 (drug content = 95.7%)

[0309] The API-NXB drug substance is expressed as the dry free base.

[0310] 600 mg / g API intermediates were prepared according to the Figure 2 procedure described in the flow chart. In step 1, the components were sieved into a suitable container in the following order: API-NXB, silica, HPMC. In step 2, the mixture from step 1 was blended. In step 3, the mixture was subjected to hot melt extrusion. In step 4, the molten extrudate from step 3 was milled into granules.

[0311] Table 10B

[0312]

[0313] Extrusion can start at a feed rate of 3 kg / h and a screw speed of 150 rpm, and then be continuously increased to a feed rate of 5 kg / h and a screw speed of 200 rpm. In addition, the water temperature at the cooling roll and the roll gap are increased from 15 °C and 0.21 mm to 17 - 18 °C and 0.5 mm. When the water temperature ≤ 15 °C, the extrudate film starts to stick due to condensation on the cooling roll.

[0314] Table 10C

[0315]

[0316] Example 11: FMI FCT Composition of Compound A

[0317] Four extrusion batches with a batch size of 17 kg were manufactured as intermediates according to the manufacturing method of Example 10 and further processed into three batches of drug product batches (1 x 100 mg and 2 x 200 mg) with a batch size of 80,000 units. Figure 2 Illustrated is a representative process flow for manufacturing 100 mg and 200 mg film-coated tablet (FCT) compositions of Compound A in Table 11A.

[0318] Table 11A

[0319]

[0320] API-NXB drug substance is expressed as dry free base.

[0321] ***The film coating suspension was prepared to have 20% solids. The coating suspension was prepared in excess to compensate for spray losses and losses in the spray system. For film coating, batches can be sub-batch coated based on the capacity of the coating machine and the available coating pans.

Claims

1. An amorphous solid dispersion comprising N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide or a pharmaceutically acceptable salt thereof, and one or more stabilizing polymers, wherein the weight ratio of the compound A or its pharmaceutically acceptable salt to the one or more stabilizing polymers is from about 5:95 to about 90:10, about 40:60, about 80:20; preferably about 60:

40.

2. The amorphous solid dispersion according to claim 1, wherein the amorphous solid dispersion is prepared by spray drying, co-grinding, hot melt extrusion, freeze drying, rotary evaporation, solvent evaporation, co-precipitation, lyophilization or any suitable solvent removal method, preferably hot melt extrusion.

3. The amorphous solid dispersion according to claim 2, wherein the amorphous solid dispersion is prepared from N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide in amorphous form, crystalline form or a mixture thereof.

4. The amorphous solid dispersion according to claim 3, wherein N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide is in the form of crystalline monohydrate Form H A , Characterized in that, When measured using CuKα radiation, an X-ray powder diffraction pattern having at least one, two, three, four or five peaks, the at least one, two, three, four or five peaks having a refractive angle 2theta (θ) value selected from 7.3, 10.7, 16.3, 16.7, 17.4, 23.0, 24.3, 25.3, 28.3, 32.0, wherein the value is plus or minus 0.2° 2θ.

5. The amorphous solid dispersion according to any one of claims 1 to 4, wherein the one or more stabilizing polymers are selected from polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone (crosslinked povidone or PVP-XL), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMC-P), carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose (NaCMC), methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyethylene glycol (PEG), polyvinyl alcohol, polyvinylpyrrolidone-vinyl acetate copolymer (copovidone or PVP / VA), polyvinyl alcohol-polyethylene glycol copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyacrylate, polymethacrylate or a mixture thereof.

6. The amorphous solid dispersion according to claim 5, wherein the stabilizing polymer is HPMC, preferably HPMC 2910.

7. The amorphous solid dispersion according to any one of claims 1 to 6, further comprising a glidant selected from silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose fatty acid ester, microcrystalline wax, yellow beeswax, white beeswax, etc. and mixtures thereof, preferably silica, more preferably colloidal silica.

8. The amorphous solid dispersion according to any one of claims 1 to 7, which further comprises a solubilizer selected from polyoxyethylene alkyl aryl ethers, polyethylene glycol fatty acid esters, D-α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid esters, alkyl sulfates or sulfonates, lecithin, polyethoxylated castor oil, and the like, and mixtures thereof.

9. The amorphous solid dispersion according to any one of claims 1 to 8, wherein N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide or a pharmaceutically acceptable salt thereof accounts for about 1% to about 90% (w / w), about 10% (w / w) to about 85% (w / w), preferably about 15% (w / w) to about 80% (w / w), about 20% (w / w) to about 75% (w / w) or about 30% (w / w) to about 60% (w / w) of the dispersion.

10. A pharmaceutical composition comprising the amorphous solid dispersion according to any one of claims 1 to 9 and optionally one or more pharmaceutically acceptable excipients selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, basic stabilizers, colorants, flavorants, preservatives, and combinations thereof.

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition comprises about 10 mg to about 300 mg of N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide or a pharmaceutically acceptable salt thereof, preferably 50 mg, 100 mg, 200 mg or 300 mg of N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to any one of claims 10 to 11, wherein the pharmaceutical composition is in the form of tablets, capsules, cachets, beads, granules, oral suspensions, oral solutions or microemulsions.

13. The pharmaceutical composition according to any one of claims 10 to 12, wherein the pharmaceutical composition is in the form of tablets or capsules, which comprises: (a) an amorphous solid dispersion of compound A in particulate form, (b) at least one intragranular excipient, (c) at least one extragranular excipient, and (d) optionally, a coating.

14. The pharmaceutical composition according to claim 13, wherein the extragranular excipient is selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, basic stabilizers, colorants, flavorants, preservatives, and combinations thereof.

15. The pharmaceutical composition according to claim 14, wherein the external excipient of the granules comprises a diluent selected from microcrystalline cellulose, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, powdered cellulose, glucose binder, dextrin, glucose excipient, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, refined caster sugar, and combinations thereof, preferably lactose, microcrystalline cellulose, or lactose and microcrystalline cellulose.

16. The pharmaceutical composition according to claim 14, wherein the external excipient of the granules comprises a disintegrant selected from sodium croscarmellose, low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpolypyrrolidone (cross-linked povidone), sodium bicarbonate, sodium starch glycolate, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and mixtures thereof, preferably sodium bicarbonate and cross-linked povidone, more preferably sodium croscarmellose.

17. A method for preparing the amorphous solid dispersion according to any one of claims 1 to 9 or the pharmaceutical composition according to any one of claims 10 to 16, which comprises preparing a mixture of N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide or a pharmaceutically acceptable salt thereof, one or more stabilizing polymers, and optionally one or more pharmaceutically acceptable excipients; heating the mixture to form a melt; extruding the melt; cooling the melt to form an amorphous solid dispersion; and optionally granulating the amorphous solid dispersion and / or compacting the granules of the amorphous solid dispersion for further processing with optionally one or more pharmaceutically acceptable excipients to form a composition suitable for a dosage form, preferably a tablet or a capsule.

18. The pharmaceutical composition according to any one of claims 10 to 16, which is used as a medicine.

19. The pharmaceutical composition according to any one of claims 10 to 16, which is used for treating cancer.

20. The pharmaceutical composition according to any one of claims 10 to 16, which is used for treating cancer, particularly for treating cancers with MAPK pathway alterations, such as KRAS mutant NSCLC (non-small cell lung cancer), KRAS mutant pancreatic cancer (e.g., KRAS mutant pancreatic ductal adenocarcinoma (PDAC)), KRAS mutant CRC (colorectal cancer), and NRAS mutant melanoma.

21. A method for treating cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to any one of claims 10 to 16.

22. The method according to claim 21, wherein the cancer has a MAPK pathway alteration, such as KRAS mutant NSCLC (non-small cell lung cancer), KRAS mutant pancreatic cancer (e.g., KRAS mutant pancreatic ductal adenocarcinoma (PDAC)), KRAS mutant CRC (colorectal cancer), and NRAS mutant melanoma.

Images