Amorphous solid dispersions containing napolafenib

Abstract

The present invention relates to the field of pharmacy, and in particular to pharmaceutical compositions comprising N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, or a pharmaceutically acceptable salt thereof. The present invention further provides processes for preparing said pharmaceutical compositions for oral administration and methods of treatment using said pharmaceutical compositions.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 370,989, filed August 10, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention provides solid amorphous dispersions 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 further provides pharmaceutical compositions or dosage forms comprising the solid amorphous dispersions, processes for preparing them, and methods of treatment therewith. The present invention further provides these pharmaceutical compositions for oral administration. [Background technology]

[0003] The RAS / RAF / MEK / ERK or MAPK pathway is a critical signaling cascade that induces cell proliferation, differentiation, and survival. Dysregulation of this pathway underlies many cases of tumorigenesis. Aberrant signaling or inappropriate activation of the MAPK pathway has been demonstrated in multiple tumor types, including melanoma, lung, and pancreatic cancer, and can occur through several different mechanisms, including activating mutations in RAS and BRAF. RAS is a superfamily of GTPases, including KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), a regulated signaling protein that can be turned on (activated) by a variety of single-point mutations known as gain-of-function mutations. The MAPK pathway is frequently mutated in human cancers, with KRAS and BRAF mutations being the most frequent (approximately 30%).

[0004] N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (Compound A) was originally described in WO 2014 / 151616 as the compound of Example 1156. It has the formula I:

[0005] [ka] It is a Raf inhibitor, particularly an inhibitor of CRAF and BRAF, having the structure: monohydrate H A Various crystalline forms of the compound of formula I or Compound A, including the form Compound A is also known as "napolafenib," are described in WO / 2020 / 230028.

[0006] Compound A may be useful in treating various cancers, particularly those harboring MAPK pathway alterations, such as KRAS-mutated NSCLC (non-small cell lung cancer), KRAS-mutated pancreatic cancer (e.g., KRAS-mutated pancreatic ductal adenocarcinoma (PDAC)), KRAS-mutated CRC (colorectal cancer), and NRAS-mutated melanoma.

[0007] There is a need to formulate Compound A into a pharmaceutical composition, particularly an oral pharmaceutical dosage form, so that the therapeutic benefits of the compound can be delivered to patients in need.The physiochemical properties of therapeutic compounds make this need a challenge to solve.Compound A is poorly soluble in aqueous media and has high permeability, which helps to address potential solubility and bioavailability issues that need to be addressed in the development of pharmaceutical dosage forms containing naporafenib.Therefore, the present invention aims to provide an exemplary solution for preparing a pharmaceutical composition containing naporafenib in the form of a solid oral dosage form that can be ingested by patients. [Brief explanation of the drawings]

[0008] [Figure 1A] 1 depicts the drug substance particle form for Compound A as free base-anhydrous (NXA). [Figure 1B]1 depicts the drug substance particle form for Compound A as the free base-monohydrate (NXB). [Figure 2]

[0023] Figure 1 illustrates a representative process flow diagram for the production of 600 mg / g Compound A (API) granules and for the addition of extragranular ingredients to produce Compound A (API) film coated tablets. Summary of the Invention

[0009] Because every active pharmaceutical ingredient (API) has its own physical, chemical, and pharmaceutical characteristics, appropriate pharmaceutical compositions and dosage forms must be individually designed for each new API.

[0010] Designing pharmaceutical compositions, pharmaceutical dosage forms, and commercially viable processes for preparing pharmaceutical compositions for Raf inhibitors, such as N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (Compound A), its pharmaceutically acceptable salts, or free base, has been challenging. These Raf inhibitors are difficult to formulate due to their physicochemical properties, such as low solubility, high permeability, and susceptibility to degradation under certain pH conditions and temperatures. These properties affect the pharmacokinetics, bioavailability, and manufacturing processes of formulations containing the Raf inhibitors of the present invention.

[0011] Therefore, there is a need to develop a suitable and robust solid pharmaceutical composition that overcomes the above problems. The present invention provides a pharmaceutical composition with enhanced drug dissolution and increased absorption. The pharmaceutical composition may further provide increased bioavailability and / or reduced inter-patient variability. Furthermore, the present invention provides a process for making the pharmaceutical composition, which provides easy scale-up, robust processing, and economic advantages.

[0012] The present invention aims to provide a formulation of Compound A that minimizes the size and / or number of tablets or capsules required for a therapeutically effective dose, ideally to fewer than four tablets or capsules, preferably only one or two tablets or capsules.

[0013] With regard to the goal of increasing the therapeutic potential of Compound A, the inventors have attempted to increase the therapeutic potential by achieving an increase in the bioavailability of Compound A in a formulation that allows for a sufficiently high drug loading (e.g., greater than 5%). In different embodiments, the drug loading is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%. It is understood that the higher the drug loading, the higher the likelihood of instability. Therefore, achieving an increase in drug loading while maintaining the physical and chemical stability of the resulting pharmaceutical product is not a trivial challenge.

[0014] The present inventors have discovered that solid dispersion formulations, such as polymer stabilized amorphous solid dispersion (PSASD) formulations, address one or more of the above objectives.

[0015] The present inventors have surprisingly found that the therapeutic potential of Compound A can be increased by formulating Compound A as an amorphous solid dispersion using one or more stabilizing polymers. The amorphous solid dispersions of the present invention allow for better solubility, faster dissolution rate, and improved bioavailability of Compound A. Amorphous solid dispersion formulations of Compound A with the stabilizing polymer hypromellose have been found to be particularly suitable for providing physically and chemically stable pharmaceutical compositions with high drug loadings of Compound A (e.g., up to 80%). The present inventors have further found that, compared to the anhydrous form of Compound A, amorphous solid dispersion formulations prepared using the monohydrate form of Compound A allow for a doubling of the drug loading in the solid dispersion (e.g., from about 30 to 60%) and a reduction in tablet size (e.g., about 70% reduction).

[0016] Considering the above obstacles and concerns, it was not a trivial matter to improve the solubility and bioavailability of Compound A and obtain a stable pharmaceutical composition suitable for commercial scale manufacture.

[0017] The aspects, advantageous features and preferred embodiments of the present invention summarized in the following paragraphs each contribute alone or in combination to solving the objects of the present invention.

[0018] 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 the one or more stabilizing polymers is about 5:95 to about 90:10, about 40:60, about 80:20, preferably about 60:40.

[0019] Item A2. The amorphous solid dispersion according to item A1, prepared by spray drying, co-milling, hot melt extrusion, freeze drying, rotary evaporation, solvent evaporation, co-precipitation, freeze drying, or any suitable solvent removal process. Preferably, the amorphous solid dispersion is made by hot melt extrusion.

[0020] Item A3. The amorphous solid dispersion according to item A1, prepared from compound A in amorphous form, crystalline form, or a mixture thereof.

[0021] Item A4. The amorphous solid dispersion according to Item A3, prepared from Compound A in crystalline form.

[0022] Item A5. The amorphous solid dispersion according to item A4, prepared from Compound A in an anhydrous crystalline form.

[0023] Item A6. The amorphous solid dispersion according to Item A5, prepared from anhydrous Form A of Compound A.

[0024] Item A7. An amorphous solid dispersion according to item A4, prepared from Compound A in a hydrate crystalline form, for example a monohydrate crystalline form.

[0025] Item A8. Compound A Monohydrate Form H of Compound A A The amorphous solid dispersion according to item A7, prepared from

[0026] Item A9. The amorphous solid dispersion according to item A1, wherein the one or more stabilizing polymers are selected from the group consisting of polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone (crospovidone or PVP-XL), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), hypromellose (HPMC), hypromellose acetate succinate (HPMC-AS), hypromellose phthalate (HPMC-P), carboxymethylcellulose, croscarmellose sodium (NaCMC), methylcellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, carboxymethylhydroxyethyl cellulose, polyethylene glycol (PEG), polyvinyl alcohol, polyvinylpyrrolidone-vinyl acetate copolymer (copovidone or PVP / VA), polyvinyl alcohol-polyethylene glycol copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyacrylates, polymethacrylates, or mixtures thereof.

[0027] Item A10. The amorphous solid dispersion according to item A9, wherein the one or more stabilizing polymers is polyvinylpyrrolidone (PVP) or polyvinylpolypyrrolidone (crospovidone or PVP XL), preferably poly(vinylpyrrolidone-co-vinyl acetate 60:40 (PVP VA64) or PVP K30.

[0028] Item A11. The amorphous solid dispersion according to item A9, wherein the one or more stabilizing polymers is croscarmellose sodium (NaCMC, Ac-Di-Sol) or low-substituted hydroxypropyl cellulose (L-HPC).

[0029] Item A12. The amorphous solid dispersion according to item A9, wherein the one or more stabilizing polymers are polymethacrylates, preferably Eudragit® L100 (methacrylic acid-methyl methacrylate copolymer (1:1)) or Eudragit® L100-55 (poly(methacrylic acid, ethyl acrylate) 1:1).

[0030] Item A13. The amorphous solid dispersion according to item A9, wherein the one or more stabilizing polymers is hypromellose (HPMC), preferably HPMC 2910.

[0031] Item A14. The amorphous solid dispersion according to item A9, wherein the one or more stabilizing polymers is hypromellose acid salt succinate (HPMC-AS), preferably HPMC-AS-L, HPMC-AS-M, or HPMC-AS-H.

[0032] Item A15. The amorphous solid dispersion according to item A14, wherein the one or more stabilizing polymers is a mixture of hypromellose (HPMC) and hypromellose acid salt succinate (HPMC-AS).

[0033] Item A16. The amorphous solid dispersion according to items A1-A15, optionally further comprising one or more pharmaceutically acceptable excipients selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, alkaline stabilizers, colorants, flavoring agents, preservatives, and combinations thereof.

[0034] Item A17. The amorphous solid dispersion according to Items A1 to A16, further comprising a glidant selected from the group consisting of silicon dioxide, 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, wherein the glidant is preferably silicon dioxide, more preferably colloidal silicon dioxide.

[0035] Item A18. The amorphous solid dispersion according to Items A1 to A16, further comprising a solubilizer selected from the group consisting of polyoxyethylene alkylaryl ethers, polyethylene glycol fatty acid esters, D-α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid esters, alkyl sulfates or sulfonates (sodium lauryl sulfate or sodium dioctyl sulfosuccinate), lecithin, polyethoxylated castor oil, and the like, and mixtures thereof.

[0036] Item A19. The amorphous solid dispersion according to any one of Items A1 to A18, wherein Compound A is present in an amount of 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.

[0037] 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 one or more stabilizing polymers in the dispersion is from about 5:95 to 90:10, preferably about 40:60, about 60:40, or about 80:20.

[0038] Item A21. A pharmaceutical composition comprising the amorphous solid dispersion according to items A1 to A20 and, optionally, one or more pharmaceutically acceptable excipients selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, alkaline stabilizers, colorants, flavoring agents, preservatives, and combinations thereof.

[0039] Item A22. The pharmaceutical composition according to item A21, in the form of a tablet, capsule, caplet, bead, granule, oral suspension, oral solution, or microemulsion, preferably in the form of a tablet.

[0040] Item A23. The pharmaceutical composition according to Items A21 to A22, comprising about 10 mg to about 300 mg of compound A, preferably 50 mg, 100 mg, 200 mg, or 300 mg of compound A.

[0041] Item A24. The pharmaceutical composition according to items A21 to A23, in the form of a tablet or capsule comprising (a) an amorphous solid dispersion of Compound A in the form of granules, (b) at least one intragranular excipient, (c) at least one extragranular excipient, and (d) optionally a coating.

[0042] Item A25. The pharmaceutical composition according to Item A24, wherein the extragranular excipient(s) comprises a diluent selected from the group consisting of microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, powdered cellulose, dextrates, dextrin, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, powdered sugar, and combinations thereof, wherein the diluent is preferably lactose, microcrystalline cellulose, or a mixture of lactose and microcrystalline cellulose.

[0043] Item A26. The pharmaceutical composition according to Items A24 to A25, wherein the extragranular excipient further comprises a disintegrant selected from the group consisting of croscarmellose sodium, low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpolypyrrolidone (crospovidone), sodium bicarbonate, sodium starch glycolate, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and mixtures thereof, and the disintegrant is preferably selected from croscarmellose sodium, sodium bicarbonate, and crospovidone, more preferably croscarmellose sodium.

[0044] Item A27. A method for preparing the pharmaceutical composition according to items A21 to A24, comprising mixing Compound A or a pharmaceutically acceptable salt thereof, or an amorphous form thereof, or a crystalline form thereof with one or more stabilizing polymers and optionally one or more pharmaceutically acceptable excipients, heating the mixture to form a molten mass, extruding the molten mass, cooling the molten mass to form a solid amorphous dispersion, and optionally granulating the solid amorphous dispersion and / or compressing the solid amorphous dispersion or granules of the solid amorphous dispersion for further processing, optionally with one or more pharmaceutically acceptable excipients, to form a composition suitable for use in dosage forms such as tablets and capsules. Preferably, the solid amorphous dispersion is milled to form granules.

[0045] Item A28. The pharmaceutical composition according to any one of Items A21 to A26 for use as a medicament.

[0046] Item A29. A pharmaceutical composition according to any one of items A21 to A26 for use in the treatment of cancer.

[0047] Item A30. The pharmaceutical composition according to any one of items A21 to A26 for use in the treatment of cancer, particularly the treatment of cancers harboring MAPK pathway alterations, such as KRAS-mutated NSCLC (non-small cell lung cancer), KRAS-mutated pancreatic cancer (e.g., KRAS-mutated pancreatic ductal adenocarcinoma (PDAC)), KRAS-mutated CRC (colorectal cancer), and NRAS-mutated melanoma.

[0048] Item A31. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to any one of Items A21 to A26.

[0049] Item A32. The method of A30, wherein the cancer harbors 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 OF THE INVENTION

[0050] 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.

[0051] 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 exists as the free base and not as a salt of Compound A.

[0052] In certain embodiments, an amorphous form of the free base of Compound A, a crystalline form of the free base of Compound A, or a mixture of amorphous and crystalline forms of Compound A may be used in preparing the amorphous solid dispersion formulations of Compound A of the present invention.

[0053] As used herein, the term "amorphous" refers to a solid form of a compound that is not substantially crystalline. Amorphous compounds do not have long-range order and do not exhibit a distinct X-ray diffraction pattern with reflections.

[0054] In one embodiment, the amorphous solid dispersion is prepared from a crystalline form of Compound A. In one embodiment, the crystalline form of Compound A used in preparing the amorphous solid dispersion of the present invention is crystalline anhydrous Form A.

[0055] Anhydrous Form A is referred to as "Form A" and is characterized in WO / 2020 / 230028, which is incorporated herein in its entirety. It can be prepared as described in Example 2 of WO / 2020 / 230028.

[0056] Anhydrous Form A of Compound A exhibits an X-ray powder diffraction pattern having at least one, two, or three characteristic peaks expressed in degrees two-theta (°2θ) at angles of 5.8°+ / −0.2°, 11.7°+ / −0.2°, and 14.8°+ / −0.2°, as measured using CuKα radiation. In another embodiment, 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°, as measured using CuKα radiation. In another embodiment, polymorph 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° as measured using CuKα radiation.

[0057] In another embodiment, the crystalline form of Compound A (free base) is crystalline monohydrate Form H of Compound A. A is.

[0058] Crystalline monohydrate form H of Compound A A is described in WO / 2020 / 230028, which is incorporated herein in its entirety, and may be prepared according to the procedure described in Example 8 of WO / 2020 / 230028. In one embodiment, monohydrate form H A exhibits an X-ray powder diffraction pattern having at least one, two, or three characteristic peaks expressed in degrees two-theta (°2θ) at angles of 7.3°+ / −0.2°, 10.7°+ / −0.2°, and 23.0°+ / −0.2°, as measured using CuKα radiation. In another embodiment, monohydrate form H Aexhibits 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°, as measured using CuKα radiation. In another embodiment, 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° as measured using CuKα radiation.

[0059] Crystalline monohydrate form H of Compound A A can be characterized by having an X-ray powder diffraction pattern having at least one, two, three, four, or five peaks having refraction angles of 2-theta (θ) values selected from 7.3, 10.7, 16.3, 16.7, 17.4, 23.0, 24.3, 25.3, 28.3, and 32.0, said values being ±0.2° 2θ, as measured using CuKα radiation. A can be further characterized as having a differential scanning calorimetry curve containing an endothermic event between about 35° C. and 135° C., exhibiting an onset of dehydration at about 94° C. Crystalline monohydrate Form H of Compound A A can be further characterized by having a thermogravimetric analysis curve that exhibits a mass loss of 3.7 wt % or less from about 43° C. to 135° C. when heated from 30° C. to 300° C. at a rate of 20° C. / min.

[0060] Monohydrate H of Compound A for preparing the amorphous solid dispersion of the present invention A The use of compound A monohydrate H as a starting material A , resulting in oral dosage forms with higher drug loadings than are possible with other solid forms of Compound A that do not use, for example, anhydrous HA.

[0061] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0062] The terms "pharmaceutical composition," "medicament," "pharmaceutical dosage form," "dosage form," "pharmaceutical formulation," and the like refer to a pharmaceutical composition that can be administered to a patient in need of treatment and can be in the form of any conventional formulation, such as, for example, a powder, granules, pills, capsules, tablets, solutions, suspensions, or patches.

[0063] The term solid dispersion generally refers to a solid-state system containing at least two components, in which one component is substantially uniformly dispersed throughout the other component. For example, a solid dispersion may be a dispersion of one or more active ingredients in a solid-state inert carrier or matrix prepared by melt, solvent, or melt-solvent methods. Without wishing to be bound by theory, in a solid dispersion, the drug may exist in a molecular, colloidal, metastable, or amorphous state. The formation of a molecular dispersion may provide a means of reducing the particle size of the drug to the near-molecular level (i.e., particle-free). When the polymer dissolves, the drug is exposed to the dissolution medium molecules or as amorphous microparticles, which can dissolve and absorb more rapidly than larger crystalline particles.

[0064] The term "solid dispersion" refers to a dispersion of a compound, particularly a drug substance or active pharmaceutical ingredient (API), within a polymer or carrier.

[0065] The term "amorphous solid dispersion" refers to a substantially amorphous molecular dispersion of a compound, particularly a drug substance or API, within a polymer or carrier. The compound may be in amorphous form, crystalline form, or a mixture prior to preparation of the solid dispersion.

[0066] Amorphous solid dispersions in which a drug substance is dispersed using one or more polymers are also known as polymer-stabilized amorphous solid dispersions (PSASDs). PSASD formulations are thermodynamically unstable solid-state systems in which one or more active ingredients are substantially uniformly dispersed throughout the other components of the formulation and stabilized using one or more polymers. In one embodiment, the amorphous solid dispersions of the present invention may be prepared from Compound A in crystalline form.

[0067] In one embodiment, the amorphous solid dispersions of the present invention may be prepared from Compound A in an anhydrous crystalline form.

[0068] In one embodiment, the amorphous solid dispersion of the present invention may be prepared from Compound A in its anhydrous crystalline form A.

[0069] In one embodiment, the amorphous solid dispersions of the present invention may be prepared from Compound A in the monohydrate crystalline form.

[0070] In one embodiment, the amorphous solid dispersion of the present invention comprises the monohydrate crystalline form Monohydrate Form H A It may be prepared from compound A, which is

[0071] Methods for Making Solid Dispersions The solid dispersion formulations according to the present invention have been found to be useful in improving the bioavailability of poorly soluble active agents, such as Compound A, by increasing their solubility.

[0072] Amorphous solid dispersions are high-energy formulations that present additional challenges due to their inherent thermodynamic instability. As a result, their successful development depends to a large extent on understanding the specific interactions involved in their stabilization (Serajuddin, ATMJ Pharm. Sci. 1999, 88, 1058-1066; Janssens, S. and Van den Mooter, GJPharm.Pharmacol. 2009, 61, 1571-1586). However, there is no universal or reliable method for selecting either a technology or polymer with guaranteed amorphous stability and improved bioavailability. Solubility parameters have been reported to aid in polymer selection. However, in general, there is no way to predict the benefits of using a particular polymer over another and / or a particular method for preparing solid dispersions in terms of providing a stable amorphous dispersion of a given drug.

[0073] Another unknown is the effect of drug loading of a given pharmaceutical formulation.Drug loading in amorphous solid dispersions has also been found to be important to the stability of any given formulation.In general, the lower the drug loading, the better the stability of the dispersion.Beyond a certain drug loading, amorphous solid dispersions have a high risk of recrystallization during shelf life, thus reducing the benefits of improving solubility and bioavailability.Therefore, although in principle, amorphous solid dispersions can theoretically improve the bioavailability of drug substances, it turns out that providing a stable pharmaceutical dosage form of drug substances in the form of amorphous solid dispersions is not a trivial task.

[0074] Despite these obstacles, the present invention provides amorphous solid dispersions comprising Compound A as the free base or as a pharmaceutically acceptable salt thereof and one or more stabilizing polymers, wherein Compound A may be successfully administered to a patient in need thereof in a bioavailable manner, and oral dosage forms of Compound A are stable.

[0075] The amorphous solid dispersions of the present invention may be formed by any conventional technique, such as spray drying, co-milling, hot melt extrusion, vacuum freeze drying, rotary evaporation, solvent evaporation, co-precipitation, lyophilization, or any suitable solvent removal process.

[0076] Without wishing to be bound by theory, the stabilizing polymer in solid dispersion may reduce the molecular mobility of the drug, so as to avoid phase separation and recrystallization of the drug during storage.However, it will be understood that the presence of certain exogenous excipients may impair the stability of the solid dispersion (for example, to remain amorphous).It has been found that the selection of polymer and process for amorphous solid dispersion plays an important role in the solubility and stabilization of the solid dispersion.However, there is no absolute method to a priori determine whether a given polymer or process provides the appropriate solubility and stability of the amorphous solid dispersion.

[0077] In one embodiment, the amorphous solid dispersion of the present application comprises Compound A and one or more stabilizing polymers selected from the group consisting of polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone (crospovidone or PVP-XL), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), hypromellose (HPMC), hypromellose acetate succinate (HPMC-AS), hypromellose phthalate (HPMC-P), carboxymethylcellulose, croscarmellose sodium (NaCMC), methylcellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, carboxymethylhydroxyethyl cellulose, polyethylene glycol (PEG), polyvinyl alcohol, polyvinylpyrrolidone-vinyl acetate copolymer (copovidone or PVP / VA), polyvinyl alcohol-polyethylene glycol copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyacrylates, polymethacrylates, or mixtures thereof.

[0078] In one embodiment, the present solid amorphous dispersion 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 may be used, such as poly(vinylpyrrolidone-co-vinyl acetate 60:40 (PVP VA64) or PVP K30.

[0079] In one embodiment, the present solid amorphous dispersion comprises Compound A and one or more stabilizing polymers, wherein the one or more stabilizing polymers is polyvinylpolypyrrolidone (crospovidone or PVP XL).

[0080] 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 croscarmellose sodium (NaCMC) or low-substituted hydroxypropyl cellulose (L-HPC).

[0081] 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 Eudragit® L100 or Eudragit® L100-55.

[0082] Eudragit® is the brand name for a range of polymethacrylic acid copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic / acrylic acid esters or their derivatives. Eudragit® L100 is an anionic copolymer of methacrylic acid and methyl methacrylate with a free carboxyl group to ester group ratio of approximately 1:1. Eudragit® L100-55 is an anionic copolymer based on methacrylic acid and ethyl acrylate with a free carboxyl group to ester group ratio of approximately 1:1.

[0083] In a preferred 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 (HPMC). Various grades of hypromellose may be used, for example, hypromellose containing various ratios of hydroxypropyl and methoxy groups. The following types of hypromellose specified in the Pharmacopoeias (Ph. Eur., USP / NF, and JP) may be used:

[0084] [Table 1]

[0085] An example of a stabilizing polymer for use 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."

[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 hypromellose acetate succinate (HPMC-AS), preferably HPMC-AS-L, HPMC-AS-M, or HPMC-AS-H.

[0087] In one 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 a mixture of hypromellose (HPMC) and hypromellose acetate succinate (HPMC-AS).

[0088] The solid amorphous dispersions of the present invention may optionally further comprise one or more pharmaceutically acceptable excipients selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, alkaline stabilizers, colorants, flavoring agents, preservatives, and combinations thereof.

[0089] 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" in the sense of being compatible with the other components of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of humans or animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and 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, alkaline stabilizers, colorants, flavoring agents, and preservatives. One skilled in the art can select one or more of the aforementioned excipients with respect to the particular desired characteristics of the solid oral dosage form by routine experimentation and without undue burden. The amount of each excipient used may vary within ranges conventional in the art. The following references, all of which are incorporated herein by reference, disclose the techniques and excipients used to formulate oral dosage forms. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0090] The solid amorphous 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. Suitable lubricants or glidants for use in the compositions of the present invention include silicon dioxide, 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 silicon dioxide, more preferably colloidal silicon dioxide.

[0091] In one embodiment, the present solid amorphous dispersion comprises Compound A, one or more stabilizing polymers, and optionally one or more pharmaceutically acceptable excipients that are glidants. In particular, it has been found that when a mixture of a glidant, such as silicon dioxide, a stabilizing polymer (e.g., HPMC), and Compound A is blended and subjected to the process of hot melt extrusion, the resulting extrudate exhibits improved grinding properties, a superior compressibility profile, and results in improved disintegration times for the resulting oral dosage form.

[0092] The amorphous solid dispersions of the present invention may optionally contain one or more solubilizers, i.e., additives that increase the solubility or dissolution rate of the pharmaceutically active ingredient in the solid dispersion or that act as pore-forming agents in the solid dispersion. Solubilizers can be selected from surfactants, nonionic copolymers, bile salts, and hydrotropes. Suitable solubilizers for use in the compositions of the present invention include cyclodextrins, poloxamers, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, alkyl sulfates or sulfonates, sodium lauryl sulfate or dioctyl sodium sulfosuccinate, lecithin, D-α-tocopheryl polyethylene glycol succinate, polyethoxylated castor oils such as Cremophor® RH 40 and Cremophor® EL / ELP, polyoxyethylene stearate, Eudragit® EPO, and Eudragit® L. 100-55, hypromellose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer such as Soluplus®, polyoxyethylene alkylaryl ethers such as polyoxyethylene stearyl ether, polyethylene glycol fatty acid esters such as PEG stearate or PEG hydroxystearate, sodium taurocholate, sodium benzoate, and the like, and combinations thereof.

[0093] The amorphous solid dispersion of the present invention may optionally contain one or more surfactants. A surfactant is a compound that can improve wetting and / or enhance dissolution of a drug. The surfactant can be selected from hydrophilic surfactants, lipophilic surfactants, or mixtures thereof. The surfactant can be anionic, nonionic, cationic, or zwitterionic surfactants. Surfactants according to the present invention include nonionic copolymers such as poloxamer 188, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl 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 lauryl sulfate, sodium dioctyl sulfosuccinate, lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, polyoxyethylene lysine oil, polyoxyethylene fatty acid glycerides, Cremophor® RH 40. EL / ELP, etc., or combinations thereof.

[0094] In some embodiments, the drug loading of Compound A in the amorphous solid dispersion is about 1% to about 90% (w / w) (e.g., 1% to 5%, 5% to 10%, 5% to 20%, 5% to 30%, 5% to 40%, 5% to 50%, 5% to 60%, 5% to 70%, 5% to 80%, 5% to 90%, 10% to 20%, 10% to 30%, 1 0%~40%, 10%~50%, 10%~60%, 10%~70%, 10%~80%, 10%~90%, 20%~30%, 20%~40%, 20%~50%, 20%~60%, 20%~70%, 20%~80%, 20%~90%, 21%~30%, 21%~34%, 21%~40%, 21%~50%, 21% ~60%, 21%~70%, 21%~80%, 21%~90%, 30%~40%, 30%~50%, 30%~60%, 30%~70%, 30%~80%, 30%~90%, 36%~40%, 36%~49%, 36%~60%, 36%~70%, 36%~80%, 36%~90%, 40%~50%, 40%~60% In some preferred embodiments, the loading percentage of Compound A 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).

[0095] In some embodiments, the amorphous solid dispersions of the present invention have a ratio of the amount by weight of Compound A to the amount by weight of one or more stabilizing polymers of about 5:95 to about 90:10, about 40:60, about 80:20, preferably about 60:40.

[0096] In one aspect, a method is provided for preparing an amorphous solid dispersion as described herein, comprising 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 molten mass, extruding the molten mass, and cooling the molten mass to form the amorphous solid dispersion (e.g., hot melt extrusion).

[0097] The resulting amorphous solid dispersion can be directly processed into a final dosage form or further processed into a final dosage form. For example, the amorphous solid dispersion can be milled, granulated, and then compressed, and then blended with one or more excipients as described herein 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, for example, binders, fillers, disintegrants, wetting agents, glidants, and lubricants, and the resulting mixture can be granulated to form granules comprising the solid dispersion and one or more excipients.

[0098] Hot Melt Extrusion Process In certain embodiments, the solid dispersions of the present invention can be made by hot melt extrusion ("hot melt extrusion"), e.g., a process in which a composition is heated and / or compressed to a molten (or softened) state and then forced through an orifice in a die, where the extruded product is formed into its final shape that solidifies upon cooling. Hot melt extrusion is simple and easy to operate, reduces energy consumption, and increases productivity.

[0099] In the hot-melt extrusion process, the blend is typically conveyed through one or more heated zones by a screw mechanism. The screw(s) are 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. This configuration creates high shear between the barrel wall and the screw fights, which thoroughly mixes and deagglomerates the various components of the powder blend. The die can be a dual-manifold, multi-manifold, or feedblock-type die. As used herein, the term extrudate refers to a hot-melt extruded composition.

[0100] 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 may be subjected to hot-melt extrusion at about 25°C to about 200°C, for example, about 25°C to about 170°C, through a twin-screw hot-melt extruder (such as a Thermo Fisher Pharma 11mm twin-screw or a Leistritz ZSE 18mm HPe-PH twin-screw). The resulting hot-melt extrusion product may be cooled, crushed, and passed through a 0.5mm screen.

[0101] In other embodiments, the mixture can be fed into a hot melt extruder having temperature zones of from about 25° C. to about 200° C., for example, from about 25° C. to about 170° C., to produce an extrudate.

[0102] Preferably, hot melt extrusion should be carried out at a temperature that allows for the melting of compound A and one or more stabilizing polymers. In some embodiments, the mixture of compound A and one or more stabilizing polymers has a glass transition temperature T g or melting temperature T m The mixture may be heated to about or above the temperature at which the solid dispersion is formed to form a liquid mixture. After the mixture is heated to form a molten mass, it may be extruded and cooled to form a solid dispersion.

[0103] The temperature and screw speed of the hot melt extruder may be selected based on, for example, the type of pharmaceutically acceptable carrier utilized to smoothly extrude the target mixture, the extrusion rate and yield meeting the desired requirements, and the desired amorphization and dispersion effects.

[0104] In some embodiments, a glidant may also be optionally included in the mixture of Compound A and one or more stabilizing polymers to enhance the grinding characteristics, compressibility profile, and disintegration time of the extrudate. Exemplary glidants include silicon dioxide in any useful or effective amount (e.g., about 1% to about 10% (w / w), e.g., about 3% (w / w)) of the solid amorphous dispersion.

[0105] The extrudate can optionally be pelletized or milled to form a solid dispersion that is amenable to further processing into a suitable unit dosage form. In some aspects, the extrudate is then pelletized and milled to produce extrudate granules. The milled / pelletized extrudate can be used for encapsulation or tableting. In certain embodiments, the milled / pelletized extrudate is sieved to form an internal phase (e.g., granular component) that can be blended with various pharmaceutically acceptable excipients, such as binders, fillers, disintegrants, wetting agents, glidants, and lubricants, to form an external phase (e.g., extragranular component), and the resulting blend is used for encapsulation or tableting.

[0106] Pharmaceutical Composition The solid amorphous dispersions of the present invention may be used to fill any one of the unit dosage forms (e.g., capsules) described herein or to be tableted.

[0107] The solid dispersion can optionally be further processed prior to filling or tableting. Exemplary further processing includes spheronizing, pelletizing, milling, injection molding, sieving, and / or calendering the solid dispersion.

[0108] The amorphous solid dispersion of the present application can optionally be subjected to a particle size reduction procedure before or after the completion of drying or cooling of the product to achieve the desired particle size and particle size distribution. Milling or micronization can be performed to achieve the desired particle size or distribution. Equipment that can be used to reduce particle size 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 granules.

[0109] The granules of the solid amorphous dispersion of the present invention may be combined with one or more pharmaceutically acceptable excipients to make other pharmaceutical compositions or final dosage forms. The one or more additional pharmaceutically acceptable excipients may be selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, alkaline stabilizers, colorants, flavoring agents, preservatives, and combinations thereof.

[0110] In one embodiment, a pharmaceutical composition of the 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, alkaline stabilizers, colorants, flavoring agents, preservatives, and combinations thereof.

[0111] The pharmaceutical compositions of the present invention may be in the form of oral dosage forms such as tablets, capsules, caplets, beads, granules, oral suspensions, oral solutions, or microemulsions, preferably in the form of tablets.

[0112] The tablets or granules of the present invention may be uncoated, or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, tablets may be coated with suitable polymers or conventional coating materials, e.g., to achieve higher stability in the gastrointestinal tract or to achieve a desired release rate. For example, tablets may be coated with hypromellose (HPMC), magnesium stearate, polyethylene glycol (PEG), polyvinyl alcohol (PVA), Opadry®, Opadry II®, or mixtures thereof. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be utilized. Tablets of any shape or size may be prepared, and they may be opaque, colored, or flavored. Specifically, the pharmaceutical compositions disclosed herein are in the form of film-coated tablets.

[0113] In one embodiment, a pharmaceutical composition of the invention comprises granules of an amorphous solid dispersion of Compound A, optionally mixed with one or more additional pharmaceutically acceptable excipients (e.g., extragranular materials), and compressed into tablets or filled into hard gelatin capsules.

[0114] In one embodiment, a pharmaceutical composition of the invention is in the form of a tablet or capsule comprising (a) an amorphous solid dispersion of Compound A in the form of granules, (b) at least one intragranular excipient, (c) at least one extragranular excipient, and (d) optionally, a coating.

[0115] The extragranular excipients may be selected from one or more, or all, of: (i) diluents; (ii) disintegrants; (iii) lubricants; and (iv) glidants.

[0116] The diluent may be present in an amount of about 10 to about 60% by weight (w / w%) of the total composition.

[0117] The disintegrant may be present in an amount of about 1 to about 10% by weight (w / w%) of the total composition.

[0118] The lubricant may be present at about 1 to about 2 weight percent (w / w%) of the total composition.

[0119] The glidant may be present at about 1 to about 3% by weight (w / w%) of the total composition.

[0120] The extragranular excipient may also be selected from one or more, or all, of: (i) a diluent such as microcrystalline cellulose, lactose, or a combination thereof; (ii) a disintegrant such as croscopovidone, croscarmellose sodium, or a combination thereof; (iii) a lubricant (e.g., sodium stearyl fumarate); and (iv) a glidant such as silicon dioxide.

[0121] The extragranular excipients may be selected from one or more, or all, of: (i) 10-60% diluent such as microcrystalline cellulose, lactose, or a combination thereof; (ii) 1-10% disintegrant such as croscopovidone, croscarmellose sodium, or a combination thereof; (iii) 1-2% lubricant (e.g., sodium stearyl fumarate); and (iv) 1-3% glidant such as silicon dioxide, where % refers to weight % (w / w) of the total composition.

[0122] The present invention provides a pharmaceutical composition comprising granules of the amorphous solid dispersion described herein and an extragranular phase.

[0123] The pharmaceutical composition of the present invention may contain one or more lubricants or glidants.In one embodiment, suitable lubricants or glidants include silicon dioxide, stearic acid, magnesium stearate, sodium stearyl fumarate, calcium stearate, talc, hydrogenated castor oil, sucrose fatty acid ester, microcrystalline wax, yellow beeswax, white beeswax, etc., and mixtures thereof.

[0124] In one embodiment, the glidant is included in either the intragranular material or the extragranular material or both. Preferably, the glidant is silicon dioxide, more preferably colloidal silicon dioxide.

[0125] In one embodiment, the concentration of the glidant ranges from about 1% to about 3% w / w of the total composition.

[0126] 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.

[0127] Pharmaceutical compositions of the invention may also include one or more disintegrants (e.g., substances or materials added to oral solid dosage forms, such as tablets, to cause rapid disintegration of the solid dosage form upon contact with moisture, thereby aiding in its de-agglomeration).

[0128] In one embodiment, suitable disintegrants include croscarmellose sodium, low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpolypyrrolidone (crospovidone), sodium bicarbonate, sodium starch glycolate, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like, and mixtures thereof, preferably sodium bicarbonate and crospovidone, more preferably croscarmellose sodium.

[0129] In one embodiment, the concentration of the disintegrant ranges from about 1% to about 10% w / w of the total composition.

[0130] The pharmaceutical composition of the present invention may contain one or more fillers. In one embodiment, suitable fillers include microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, powdered cellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, powdered sugar, etc., and mixtures thereof.

[0131] In one embodiment, the concentration of the filler ranges from about 15% to about 60% w / w of the total composition, preferably from about 10% to about 40% w / w, and more preferably about 37% w / w.

[0132] The pharmaceutical composition of the present invention may contain one or more diluents.In one embodiment, suitable diluents include microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, powdered cellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, powdered sugar, etc., and mixtures thereof, preferably lactose, microcrystalline cellulose, or lactose and microcrystalline cellulose.

[0133] In one embodiment, the concentration of the diluent ranges from about 15% to about 60% w / w of the total composition, preferably from about 10% to about 40% w / w, and more preferably about 37% w / w.

[0134] Dosage and Administration The pharmaceutical compositions described herein may be used in methods of treatment in which an effective amount of Compound A is administered to a patient. The pharmaceutical compositions described herein may be used to treat cancer, particularly cancers harboring MAPK pathway alterations, such as KRAS-mutated NSCLC (non-small cell lung cancer), KRAS-mutated pancreatic cancer (e.g., KRAS-mutated pancreatic ductal adenocarcinoma (PDAC)), KRAS-mutated CRC (colorectal cancer), and NRAS-mutated melanoma.

[0135] For administration to animal or human subjects, the pharmaceutical composition comprises an effective dosage of Compound A. Formulations may be prepared using conventional methods depending, for example, on the subject to be treated, the mode of administration, and the type of treatment desired (e.g., prevention, prophylactic treatment, or therapy).

[0136] Compound A may be present in an amount of a total of 1 to 90% by weight of the total weight of the composition.

[0137] Preferably, the pharmaceutical composition may be provided in a dosage form suitable for oral administration, including, but not limited to, hard capsules (e.g., hard gelatin capsules or hard hydroxypropylmethylcellulose capsules), soft gelatin capsules, tablets, caplets, enteric-coated tablets, chewable tablets, enteric-coated hard gelatin capsules, enteric-coated soft gelatin capsules, minicapsules, lozenges, films, strips, gelcaps, sugar-coated tablets, suspensions, syrups, or powders. The compositions may be formulated according to conventional pharmaceutical practice.

[0138] Dosage levels can depend on the nature of the condition, drug efficacy, the condition of the patient, the judgment of the practitioner, and the frequency and mode of administration. The unit dosage form can be administered, for example, one to four times daily (e.g., once, twice, three times, or four times daily) to achieve any of the daily doses described herein.

[0139] In one embodiment, the present invention provides a pharmaceutical composition in a unit dosage form for oral administration, comprising 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 dosages include 50 mg, 100 mg, 200 mg, or 300 mg of Compound A.

[0140] The term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage form, such as a tablet, caplet, hard capsule, or soft capsule, containing a predetermined amount of drug.

[0141] An "effective" amount refers to an amount of drug sufficient to treat, prevent, or ameliorate a condition in a subject or patient. An effective amount of Compound A used in the practice of the present invention for the therapeutic management of a condition may be determined and adjusted by one skilled in the art to provide an appropriate amount and administration regimen depending, for example, on one or more of the mode of administration, the patient's age, weight, sex, and / or general health condition.

[0142] The terms "treat," "treating," or "treatment" of any disease or disorder refer to ameliorating the disease or disorder (e.g., slowing, halting, or alleviating the onset of the disease or at least one of its clinical symptoms). Additionally, these terms refer to alleviating or improving at least one physical parameter, including parameters that may not be discernible to the patient, and refer to modulating the disease or disorder physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or physically and physiologically.

[0143] The terms "prevent," "preventing," or "prevention" of any disease or disorder refers to delaying the onset or development or progression of the disease or disorder.

[0144] As used herein, the term "about" is intended to provide flexibility to the endpoints of a numerical range, with the understanding that a given value may be "slightly above" or "slightly below" the endpoint to account for variations that may be found in measurements taken between different instruments, samples, and sample preparations. The term typically means within 10%, preferably within 5%, and more preferably within 1% of a given value or range.

[0145] The terms "pharmaceutical composition" or "formulation" may be used interchangeably herein and refer to a physical mixture containing therapeutic compounds to be administered to a mammal, e.g., a human, to prevent, treat, or control a particular disease or disorder affecting the mammal. These terms also encompass intimate physical mixtures formed, for example, at elevated temperatures and pressures.

[0146] The term "oral administration" refers to any method of administration in which a therapeutic compound can be administered via the oral route by swallowing, chewing, or sucking an oral dosage form. Such oral dosage forms are traditionally intended to release and / or deliver an active agent substantially beyond the mouth and / or buccal cavity into the gastrointestinal tract.

[0147] The term "therapeutically effective amount" of a compound, as used herein, refers to an amount that elicits a biological or medical response in a subject, e.g., an amount that alleviates symptoms, ameliorates a disease, or slows or retards the progression of a disease. The term "therapeutically effective amount" also refers to an amount of a compound that, when administered to a subject, is effective to at least partially alleviate and / or ameliorate a disease, disorder, or condition. The term "effective amount" refers to an amount of a compound of interest that elicits a biological or medical response in a cell, tissue, organ, system, animal, or human that is desired by a researcher, physician, or other clinician.

[0148] The term "comprising" is used herein in its open-ended, non-limiting sense unless otherwise specified. In more limited embodiments, "comprising" can be replaced by "consisting of," which is no longer open-ended. In its most limited form, each embodiment may include only the features or values listed.

[0149] Abbreviation %w / w Percent weight to weight ℃ Celsius temperature API Active Pharmaceutical Ingredient API-NXB (or NXB) monohydrate H A Compound A in the form API-NXA (or NXA) Compound A in the form of Anhydrous Form A API-GR (from Figure 2) Granules containing compound A ASD Amorphous Solid Dispersion AUC Area under the time curve AUCinf AUC from time 0 to infinity AUClast AUC up to the last measurable time Cmax maximum concentration Cellulose HP-M 603 Hydroxypropyl methylcellulose Cellulose MK GR Microcrystalline Cellulose (MCC) Granules CV% Coefficient of variation (%) CSF clinical trial form (preparation) DR dissolution rate DSC Differential Scanning Calorimetry FaSSIF fasting artificial intestinal fluid FCT film-coated tablets FeSSIF fed state artificial intestinal fluid g / min grams per minute HME Hot Melt Extrusion HPLC High-Performance Liquid Chromatography HR-XRPD High-resolution X-ray powder diffraction INCI International Nomenclature of Cosmetic Ingredients INN International Nonproprietary Name IPC in-process control Kg / g / mg / ng / μg kilogram / gram / milligram / nanogram / microgram kN kilonewton LCMS Liquid Chromatography / Mass Spectrometry Lactose SD (or Lactose Spray in Figure 2) Lactose Spray Drying LOD Loss on drying MEPC Microemulsion Preconcentrate Formulation MG / G milligrams / grams mL / L milliliters per liter MRT average residence time Na-CMC-XL Sodium Carboxymethylcellulose nm / μm nanometer / micrometer PCS Photon Correlation Spectroscopy Ph.Eur. European Pharmacopoeia PK Pharmacokinetics PSASD Polymer-Stabilized Amorphous Solid Dispersion PSD particle size distribution RH Relative Humidity Rpm Revolutions per minute RRT Relative Retention Time RT room temperature SD and RSD Standard deviation and relative standard deviation SEM Scanning Electron Microscope SLS Sodium Lauryl Sulfate TFA trifluoroacetic acid TGA thermogravimetric analysis Tmax Time to reach maximum concentration (Cmax) US ultrasonic treatment USP United States Pharmacopoeia USP / NF United States Pharmacopeia / National Formulary w / v weight to volume w / w Weight to weight XRPD X-ray powder diffraction [Example]

[0150] The following examples are illustrative of the present invention and provide support for the disclosure of the present invention without limiting the scope of the invention.

[0151] Example 1: Characterization of various physical forms of Compound A Several physical forms of Compound A were analyzed, including the free base, tartrate, and tosylate salts. A summary of the properties of these physical forms is shown in Table 1A.

[0152] [Table 2]

[0153] The tartrate salt form was found to be the least stable of the three and was hygroscopic. The free base was found to be as stable and hygroscopic as the tosylate salt. However, while the free base has at least two polymorphic forms, the tosylate salt does not exhibit polymorphism issues. The tosylate salt was not found to offer significant improvement in solubility in aqueous media and may pose potential toxicity risks during processing. The different physical forms of Compound A shown above exhibit similar poor solubility.

[0154] Compound A has very limited solubility at all pH levels. The solubility of the amorphous free base, crystalline hydrate, and crystalline tosylate forms of Compound A is shown in Table 1B. Table 1B shows several pH-dependent solubility profiles, demonstrating that Compound A has limited solubility even at low pH levels.

[0155] [Table 3]

[0156] The photostability of the crystalline hydrate and crystalline tosylate forms of Compound A under photo or light stress is shown in Table 1C. Table 1C shows that Compound A as the crystalline hydrate and crystalline tosylate salt is stable as a bulk solid under light stress, but is susceptible to degradation under light stress in solution form. Table 1D shows that Compound A as the crystalline tosylate salt is stable as a bulk solid under thermal stress at room temperature (RT), 50°C, and 80°C for 5 days. Table 1E shows that Compound A as the crystalline tosylate salt is susceptible to degradation in solution / suspension form when exposed to low pH under heating.

[0157] [Table 4]

[0158] [Table 5]

[0159] [Table 6]

[0160] It can therefore be seen from the above that selecting which particular form of Compound A to process into an oral dosage form suitable for administration to a patient in need of treatment is not a trivial task.

[0161] Example 2: Pharmacokinetics of Compound A in Salt and Free Base Form Compositions The pharmacokinetics of Compound A in dogs were investigated after a single oral dose of 100 mg / kg Compound A as the tosylate salt in a surfactant suspension, as the free base in a surfactant suspension, and as the free base in a microemulsion, as summarized in Tables 2A and 2B. Dogs were fasted overnight from their regular diet for approximately 4 hours after dosing at each dose. Each dog received a 100 mg / kg (4 mL / kg) oral gavage dose followed by a 10 mL water washout. Compound A concentrations in plasma samples were quantified by liquid chromatography / mass spectrometry.

[0162] [Table 7]

[0163] [Table 8]

[0164] Overall, in dogs, the free base in microemulsion yielded the highest AUC (93700 h ng / mL), followed by the tosylate salt in suspension (AUC = 48200 h ng / mL) and the free base in suspension (AUC = 4370 h ng / mL). However, the composition of Test Group 3 was found to be a relatively unstable microemulsion.

[0165] Example 3: Pharmacokinetics of Compound A in various formulations The pharmacokinetics of Compound A in dogs were investigated after a single oral dose of 30 mg / kg Compound A as the tosylate salt in a polymer-enriched suspension (Steps A, B, C), as a solid dispersion tablet of the free base (Step D), and as a microemulsion of the free base (Step E), as summarized in Tables 3A and 3B.

[0166] Preparation of dosage formulations For Steps A-C, an appropriate amount of the drug substance, i.e., Compound A crystalline tosylate salt, was weighed into an appropriate container. A 30 mg / kg dose (40.3 mg / kg of tosylate salt) was weighed for each dog separately in a separate container, and a vehicle of 0.2 M Na2HPCO4 and 0.1 M aqueous citric acid was added at 3 mL / kg to prepare each formulation. The vehicles were enriched with 1% (w / v) Eudragit® EPO in Step A, 1% (w / v) hydroxypropyl cellulose (HPC) in Step B, and 1% (w / v) Kolliphor® RH40 in Step C. The resulting suspensions were stored at ambient temperature (18-30°C) and administered within 15-30 minutes of formulation preparation. For Step D, amorphous solid dispersion tablets containing 300 mg of Compound A were prepared according to Example 10.

[0167] In Step E, an active microemulsion preconcentrate (MEPC) of Compound A was prepared at 100 mg / mL (inactive MEPC components: ethanol, PEG 400, Maisine CC, Kolliphor RH 40). Formulations were prepared by measuring 0.3 mL / kg of Compound A MEPC into 0.7 mL / kg of water for each dog in a separate container to generate the microemulsion. The corresponding concentration was 30 mg / mL Compound A at a dose of 30 mg / kg. Formulations were stored at ambient temperature (18-30°C) and administered within 15-30 minutes of preparation.

[0168] Dogs were fasted overnight from regular chow for approximately 4 hours after dosing in each phase. During phases A, B, and C, six conscious dogs received the suspension formulation (3 mL / kg) by oral gavage, followed by a gavage line flush with 2 mL / kg of water for a total volume of 5 mL / kg. During phase D, each dog received one tablet orally, followed by a gavage of pH 2.6 buffer at 3 mL / kg and a gavage line flush with 2 mL / kg of water for a total volume of 5 mL / kg. During phase E, six conscious dogs received the microemulsion (1 mL / kg) by oral gavage, followed by a gavage of pH 2.6 buffer at 3 mL / kg and a gavage line flush with 1 mL / kg of water for a total volume of 5 mL / kg.

[0169] [Table 9]

[0170] [Table 10]

[0171] After oral dose administration, serial blood samples were collected up to 96 hours post-dose. After each sample was collected, plasma was generated by centrifugation, and all plasma samples were analyzed using an appropriate LC-MS / MS assay with a lower limit of quantitation (LLOQ) of 1.0 ng / mL of Compound A.

[0172] Comparing AUClast / dose, the exposure after tablet administration of Formulation D (amorphous solid dispersion formulation) was significantly higher (AUClast / D 476±266) than that after oral gavage of Formulation A (Eudragit formulation) (AUClast / D 68.3±39.8), Formulation C (AUClast / D 140±29.4), and Formulation B (HPC formulation) (AUClast / D 167±30.0), but significantly lower than that after oral gavage of Formulation E (MEPC formulation) (AUClast / D 2250±119). However, microemulsions were observed to be relatively unstable, and the MEPC formulation may be impractical for therapeutic use due to the large amount of lipid vehicle required per dose.

[0173] Example 4: Pharmacokinetics of Compound A in ASD formulation Amorphous solid dispersion (ASD) formulations of Compound A were evaluated as follows: In a crossover study in dogs, the pharmacokinetics of hot-melt extruded (HME) and spray-dried (SD) solid dispersions as suspensions were evaluated against a micronized Compound A (API) suspension (as a reference), as summarized in Tables 4A and 4B, using a nominal dose of 60 mg / kg. Hydroxypropyl methylcellulose (HPMC / hypromellose) was the stabilizing polymer used in the hot-melt extruded ASD. Copovidone (PVP VA64) and Eudragit® EPO were the stabilizing polymers used in the spray-dried ASD.

[0174] Dogs were fasted overnight from regular chow until 4 hours after dosing. Each dog was adjusted with 2 mL / kg of phosphate-citrate buffer, pH 2.6, by oral gavage, and the gavage line was flushed with 5 mL / kg. Immediately thereafter, each formulation was administered by oral gavage at 5 mL / kg of each suspension, followed by a 5 mL water flush to ensure the formulation was removed from the gavage tube.

[0175] [Table 11]

[0176] [Table 12]

[0177] Compared with the micronized API formulation, the bioavailability of the hot-melt extruded and spray-dried solid dispersion formulations was found to be 3.7-fold and 2.2-fold higher, respectively. The hot-melt extruded and spray-dried amorphous solid dispersion formulations were comparable, and no excipient-related safety concerns were identified. Improved pharmacokinetic properties were observed with the HPMC-based hot-melt extruded formulation. The spray-dried amorphous solid dispersion formulation was found to have poor stability and could not be easily densified by roller compaction or compressed into tablets.

[0178] Example 5: Clinical Trial Formulation of Compound A Drug-polymer mixtures of various compositions were prepared by hot melt extrusion (HME) in a Micro Extruder and evaluated for amorphous stability and compatibility with excipients, for example as in Example 8.

[0179] Of the polymers evaluated, hypromellose-based ASDs (e.g., HPMC2910) and copovidone-based ASDs with a 30% drug load were identified as the most suitable, particularly in terms of amorphous stability and excipient compatibility. ASDs containing these polymers were found to be amorphous by XRPD, remained physically and chemically stable upon short-term storage (1–2 weeks), and could be further developed to provide tablets with a 50 mg strength. HPMC-based tablets exhibited faster dissolution rates and higher recoveries compared to copovidone-based tablets, and maintained supersaturation for up to 2 hours.

[0180] A clinical trial formulation (CSF-1) supplied as tablets in 50 mg (550 mg tablets) and 100 mg (1100 mg tablets) strengths with a dose-proportional composition containing 9.1% Compound A, 21% hypromellose 2910, 55.6% microcrystalline cellulose, 10% crospovidone, 3.3% colloidal silica, and 1% magnesium stearate was developed for further stability testing under International Council for Harmonization (ICH) guidelines and a supportive shelf life.

[0181] Example 6: Animal studies to optimize the amorphous solid dispersion composition of Compound A Three animal studies were conducted to further understand the in vivo behavior of amorphous solid dispersion (ASD) compositions containing Compound A (API). In Dog Study 1, fasted dogs were administered four different compositions at doses of 30 mg / kg or 10 mg / kg, each with a drug load of 30-60%. The dogs were pretreated with phosphate-citrate buffer, pH 2.6, and the compositions were administered dispersed in water. In Dog Study 2, fasted dogs were administered three different compositions at doses of 30 mg / kg, each with a drug load of 60%. The dogs were pretreated with pentagastrin, and the compositions were administered dispersed in water. In Dog Study 3, fasted dogs were administered four different compositions. Formulations C1, C2, and C3 were administered at 10 mg / kg dispersed in water. Formulation C4 was administered as a neat tablet. After administration, the dogs were given phosphate-citrate buffer pH 2.6 by oral gavage to wash out. A summary of the pharmacokinetic data from the dog study is shown in Table 6.

[0182] [Table 13-1]

[0183] [Table 13-2]

[0184] In all studies, interanimal variability was moderate to high for all formulations. The mean AUClast and Cmax of API in plasma were comparable across all treatment groups within each study. However, significant differences were observed between studies, including pre-dose treatment of dogs (to normalize gastric pH) that significantly affected exposure and plasma concentrations. In Study 2, dogs were pre-treated with 6 μg / kg pentagastrin, and in Studies 1 and 3, dogs received 2 ml / kg of phosphate citrate buffer (pH 2.6) prior to dose administration.

[0185] Based on these studies, an HPMC-based amorphous solid dispersion composition with a drug loading of 60% was found to have optimal properties.

[0186] Example 7: Effect of Drug Substance Characteristics on Drug Product Properties Polymers such as hypromellose (HPMC) and various physical forms, such as anhydrous forms (referred to herein as "Compound A-NXA") and monohydrate forms (referred to herein as "Compound A-NXA"), A Form (referred to herein as Compound A-NXB)) with Compound A were prepared as separate mixtures and processed into amorphous solid drug dispersions using hot melt extrusion.

[0187] Preblends containing Compound A in anhydrous form have bulk densities between 0.07 and 0.11 g / cm 3 The flow function was 1.5-1.8. This was very cohesive, making it difficult to maintain uniform feeding into the extruder. Monohydrate Form H of Compound A A The pre-blend containing 0.33 g / cm has a higher bulk density and is more preferred. 3 The flow function was 2.2 to 2.3, which enabled uniform feeding into the extruder. As shown in Figures 1A and 1B, the anhydrous form of Compound A is the H modification of Compound A, which has a cubic particle morphology. A Unlike , it has a very fine needle-like crystal structure.

[0188] Therefore, the modification H of compound A A It has been found that the amorphous solid dispersion prepared from provides optimal flow rate of the pre-blend during processing, for example, in the hot melt extrusion process of the present invention.

[0189] Thus, the present invention provides the use of a crystalline form of Compound A that is not fine, needle-like in shape, for use in a method for preparing an amorphous solid dispersion comprising Compound A.

[0190] Example 8: Optimization of tablet formulations containing Compound A Optimization of a tablet formulation according to the present invention can be carried out as follows.

[0191] In particular, certain tablets prepared using amorphous solid dispersions prepared from the anhydrous form of Compound A and hypromellose were found to have several physical defects. In some cases, hairline cracks were observed on the sidewalls of such tablets after overnight storage. Film-coating such tablets was also difficult due to the lack of uniformity in the tablet content of the blend and some cases of rapid tablet disintegration within 5–10 seconds. Furthermore, tablets prepared using amorphous solid dispersions prepared from the anhydrous form of Compound A and hypromellose could only accommodate a low drug load, resulting in large tablets that were difficult to swallow. This resulted in a large tablet burden for patients, especially at high recommended doses, and consequently a lack of patient compliance. For example, the total weight of a tablet containing only a 9.1% drug load of Compound A (100 mg of Compound A) was 1100 mg, while the tablet size of tablets prepared from the anhydrous form of Compound A was large (20 × 10.6 mm).

[0192] Surprisingly, monohydrate H was used to prepare amorphous solid dispersions. ABy using Compound A in anhydrous form, the drug loading in the amorphous solid dispersion could be significantly increased. Thus, compared to the 100 mg tablet (20 × 10.6 mm) obtained from the amorphous solid dispersion using Compound A in anhydrous form, the drug loading in the amorphous solid dispersion containing Compound A could be doubled (from about 30% to 60%) by 200 mg tablets (17 × 6.7 mm), and the size of the tablet could be significantly reduced (up to 70%). Also, the monohydrate H A Tablets made from amorphous solid dispersions prepared from Compound A in the form were physically robust enough to be film coated.

[0193] Compound A monohydrate H A Amorphous solid dispersions prepared in various morphologies and polymers (HPMC2910, HPMC-AS-L, HPMC-AS-H, Eudragit® L100-55), melt-extruded at three different drug loadings (40%, 60%, and 80%), and milled to powder were investigated for stability and dissolution rate studies.

[0194] The two most promising PSASD powders (60% API / 40% HPMC2910 and 60% API / 30% HPMC-AS-L / 10% HPMC2910) were further developed into tablets and evaluated for adequate compressibility / processability, fast to moderately fast disintegration time, excipient compatibility, and film-coating compatibility. A range of single doses varying from 50 to 300 mg was examined for both variants. The HPMC variant was selected based on improved chemical stability and compatibility.

[0195] Film-coated tablets (e.g., 50 mg and 200 mg strength tablets) could be developed and coated with Opadry II.

[0196] Several deficiencies identified in the CSF-2 tablet formulation, most related to processability, compressibility, and in vitro performance (disintegration time / dissolution rate), were addressed in the FMI tablet formulation. The addition of silicon dioxide to the extrudate, along with HPMC, improved the milling characteristics of the extrudate, resulting in a better compressibility profile and improved disintegration time. Furthermore, microcrystalline cellulose was added to the outer phase of the final blend. These applications resulted in a more optimal particle size distribution of the extrudate and an overall improvement in tablet compression. Furthermore, sodium bicarbonate and crospovidone were replaced with croscarmellose sodium in the CSF-2 tablets to facilitate tablet disintegration.

[0197] The compositions of the 100 mg CSF1, 200 mg CSF2, and 200 mg FMI tablets are shown in Table 8. The manufacturing process for the drug product involves the unit operations of pre-blending the drug and polymer, hot-melt extrusion, pelleting, and milling to obtain a powdered amorphous solid dispersion (ASD). This is followed by final blending with excipients and lubricants, compression into tablets, and film coating. No special packaging or equipment was required for the development of the tablets as a solid dosage form.

[0198] [Table 14]

[0199] Example 9: FCT Composition of Compound A FIG. 2 shows a representative process flow diagram for producing film-coated tablets (FCT) of Compound A (API) by producing 600 mg / g Compound A (API) granules and adding extragranular ingredients.

[0200] In FIG. 2, HPM603 refers to "HPMC603," also known as HPMC2910.

[0201] Granules containing 60 wt% Compound A (where wt% refers to the weight of A compared to the total weight of the granule) can be prepared according to Table 9A.

[0202] Hot melt extrusion was carried out using a Leistritz 18 mm twin screw extruder with a batch size of 25 kg of pre-blend. The hot melt extrusion conditions are shown in Table 9B.

[0203] [Table 15]

[0204] [Table 16]

[0205] After extrusion, the extrudate was ground using a Frewitt hammer mill (hammer forward). The ground extrudate was tested for granule assay, bulk / tap density, particle size distribution (PSD), loss on drying (LOD), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) according to criteria.

[0206] A total of 10 kg of ground extrudate was used to prepare the final blend. A total of 17.69 kg was available for compression, divided into 50 mg (6 kg final blend = 40,000 tablets) and 300 mg (11.5 kg final mixture = 12,777 tablets) dosage strengths. Compression into tablets was performed in a rotary press (Fette 1200i) equipped with eight punches.

[0207] Example 10: Preparation process of intermediate granules of compound A FIG. 2 shows a representative process flow diagram for producing film-coated tablets (FCT) of Compound A (API) by producing 600 mg / g Compound A (API) granules and adding extragranular ingredients.

[0208] The batch formulation in Table 10A is representative for 1 kg of Compound A granules (API GR). The processing conditions for hot melt extrusion are shown in Table 10B. The batch size of the granules (used as intermediates) depends on clinical requirements and / or available starting materials. The weights of the individual components correspond proportionally to the compositions listed.

[0209] [Table 17]

[0210] A 600 mg / g API intermediate was prepared according to the procedure depicted in the flowchart in Figure 2. In step 1, the ingredients are sieved into a suitable container in the following order: API-NXB, silicon dioxide, and HPMC. In step 2, the mixture from step 1 is blended. In step 3, the mixture is hot-melt extruded. In step 4, the melt extrudate from step 3 is milled to form granules.

[0211] [Table 18]

[0212] Extrusion began with a feed rate of 3 kg / h and a screw speed of 150 rpm, which was then continuously increased to a feed rate of 5 kg / h and a screw speed of 200 rpm. The chill roll temperature was then increased from 15°C to 17-18°C, and the roll gap was increased from 0.21 mm to 0.5 mm. At water temperatures below 15°C, condensation on the chill roll caused the extrudate film to begin to stick.

[0213] [Table 19]

[0214] Example 11: FMI FCT composition of Compound A Four extrusion batches with a batch size of 17 kg were produced according to the manufacturing process intermediates of Example 10 and further processed into three pharmaceutical batches (1 x 100 mg and 2 x 200 mg) with a batch size of 80,000 tablets. A representative process flow for producing the 100 mg and 200 mg film-coated tablet (FCT) compositions of Compound A in Table 11A is shown in Figure 2.

[0215] [Table 20]

Claims

1. 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 Compound A or a pharmaceutically acceptable salt thereof to the one or more stabilizing polymers is from about 5:95 to about 90:10, about 40:60, about 80:20, and preferably about 60:

40.

2. 10. The amorphous solid dispersion of claim 1, made by spray drying, co-milling, hot melt extrusion, freeze drying, rotary evaporation, solvent evaporation, co-precipitation, lyophilization, or any suitable solvent removal process, preferably hot melt extrusion.

3. 3. The amorphous solid dispersion of claim 2 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. crystalline monohydrate Form H, wherein N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide is characterized by having an X-ray powder diffraction pattern having at least one, two, three, four, or five peaks having refraction angles of 2-theta (θ) values selected from 7.3, 10.7, 16.3, 16.7, 17.4, 23.0, 24.3, 25.3, 28.3, and 32.0, as measured using CuKα radiation. Ａ and the value is ±0.2° 2θ.

5. 5. The amorphous solid dispersion of any one of claims 1 to 4, wherein the one or more stabilizing polymers are selected from the group consisting of polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone (crospovidone or PVP-XL), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), hypromellose (HPMC), hypromellose acetate succinate (HPMC-AS), hypromellose phthalate (HPMC-P), carboxymethylcellulose, croscarmellose sodium (NaCMC), methylcellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, carboxymethylhydroxyethyl cellulose, polyethylene glycol (PEG), polyvinyl alcohol, polyvinylpyrrolidone-vinyl acetate copolymer (copovidone or PVP / VA), polyvinyl alcohol-polyethylene glycol copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyacrylates, polymethacrylates, or mixtures thereof.

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

7. 7. The amorphous solid dispersion of any one of claims 1 to 6, further comprising a glidant selected from the group consisting of silicon dioxide, 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 silicon dioxide, more preferably colloidal silicon dioxide.

8. 8. The amorphous solid dispersion of any one of claims 1 to 7, further comprising a solubilizer selected from the group consisting of polyoxyethylene alkylaryl 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. 9. The amorphous solid dispersion of claim 1, wherein N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, or a pharmaceutically acceptable salt thereof, comprises 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) of the amorphous solid dispersion.

10. 10. A pharmaceutical composition comprising the amorphous solid dispersion of 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, alkaline stabilizers, colorants, flavoring agents, preservatives, and combinations thereof.

11. 11. The pharmaceutical composition of claim 10, comprising 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 of any one of claims 10 to 11, in the form of a tablet, capsule, caplet, beads, granules, oral suspension, oral solution, or microemulsion.

13. 13. The pharmaceutical composition of any one of claims 10 to 12, in the form of a tablet or capsule comprising (a) an amorphous solid dispersion of Compound A in the form of granules, (b) at least one intragranular excipient, (c) at least one extragranular excipient, and (d) optionally, a coating.

14. 14. The pharmaceutical composition of claim 13, wherein the extragranular excipient is selected from solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, alkaline stabilizers, colorants, flavoring agents, preservatives, and combinations thereof.

15. 15. The pharmaceutical composition of claim 14, wherein the extragranular excipient comprises a diluent selected from the group consisting of microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, powdered cellulose, dextrates, dextrin, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, powdered sugar, and combinations thereof, preferably lactose, microcrystalline cellulose, or lactose and microcrystalline cellulose.

16. 15. The pharmaceutical composition of claim 14, wherein the extragranular excipient comprises a disintegrant selected from the group consisting of croscarmellose sodium, low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpolypyrrolidone (crospovidone), sodium bicarbonate, sodium starch glycolate, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and mixtures thereof, preferably sodium bicarbonate and crospovidone, more preferably croscarmellose sodium.

17. 17. A process for preparing the amorphous solid dispersion of any one of claims 1 to 9 or the pharmaceutical composition of any one of claims 10 to 16, comprising the steps of 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 molten mass; extruding the molten mass; cooling the molten mass to form a solid amorphous dispersion; and optionally granulating the solid amorphous dispersion and / or compressing granules of the solid amorphous dispersion to form a composition suitable for use in a tablet or capsule dosage form, optionally for further processing with one or more pharmaceutically acceptable excipients.

18. A pharmaceutical composition according to any one of claims 10 to 16 for use as a medicament.

19. A pharmaceutical composition according to any one of claims 10 to 16 for use in the treatment of cancer.

20. 17. The pharmaceutical composition of any one of claims 10 to 16 for use in the treatment of cancer, in particular the treatment of cancers harboring MAPK pathway alterations such as KRAS-mutated NSCLC (non-small cell lung cancer), KRAS-mutated pancreatic cancer (e.g., KRAS-mutated pancreatic ductal adenocarcinoma (PDAC)), KRAS-mutated CRC (colorectal cancer), and NRAS-mutated melanoma.

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

22. 22. The pharmaceutical composition of claim 21, wherein the cancer harbors MAPK pathway alterations, such as KRAS-mutated NSCLC (non-small cell lung cancer), KRAS-mutated pancreatic cancer (e.g., KRAS-mutated pancreatic ductal adenocarcinoma (PDAC)), KRAS-mutated CRC (colorectal cancer), and NRAS-mutated melanoma.

Images