Composition containing sotracib

Abstract

This specification provides amorphous solid dispersions comprising an amorphous form of sotrasib and a matrix polymer. This specification also provides a process for preparing the disclosed amorphous solid dispersions, as well as pharmaceutical compositions comprising the disclosed amorphous solid dispersions and methods for using the disclosed amorphous solid dispersions.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 505,374, filed May 31, 2023, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancers. It encodes a guanosine triphosphatase (GTPase) that cycles between an active guanosine triphosphate (GTP)-bound state and an inactive guanosine diphosphate (GDP)-bound state to control signal transduction. See, for example, Simanshu DK, Nissley DV, McCormick F. “RAS proteins and their regulators in human disease” in Cell 2017;170:17 - 33.

[0003] KRAS G12C mutations occur in approximately 13% of non-small cell lung cancers (NSCLCs) and 1-3% of colorectal cancers and other solid tumors. For example, Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. “Drugging the undruggable RAS; mission possible?” in Nat Rev Drug Discov 2014;13:828-51; Biernacka A, Tsongalis PD, Peterson JD, et al. “The potential utility of re-mining results of somatic mutation testing:KRAS status in lung adenocarcinoma”, Cancer Genet 2016;209:195-8;Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. “Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer” in Pathol Res Pract 2009;205:858-62 and Ouerhani S, Elgaaied ABA. “The mutational spectrum of HRAS,KRAS,NRAS and FGFR3 genes in See "Bladder Cancer," Cancer Biomark 2011-2012;10:259-66.

[0004] Sotrasiv (also known as AMG 510 and marketed as LUMAKRAS® or LUMYKRAS®) is a KRAS G12C It is a small molecule that specifically and irreversibly inhibits G12C mutations and is approved for the treatment of G12C-mutated cancers. Sotrasib has the following chemical structure. [ka] This compound has a chiral center in the atrop isomer and is more active in the (M)-configuration (shown above) than in the (P)-configuration of the target protein. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Simanshu DK, Nissley DV, McCormick F. “RAS proteins and their regulators in human disease”, Cell 2017;170:17-33 [Non-Patent Document 2] Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. “Drugging the undruggable RAS: mission possible?”, Nat Rev Drug Discov 2014;13:828-51 [Non-Patent Document 3] Biernacka A, Tsongalis PD, Peterson JD, et al. “The potential utility of re-mining results of somatic mutation testing:KRAS status in lung adenocarcinoma”, Cancer Genet 2016;209:195-8 [Non-Patent Document 4] Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. “Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer”, Pathol Res Pract 2009;205:858-62 [Non-Patent Document 5] Ouerhani S, Elgaaied ABA. “The mutational spectrum of HRAS,KRAS,NRAS and FGFR3 genes in bladder cancer”, Cancer Biomark 2011-2012;10:259-66 [Overview of the project] [Problems that the invention aims to solve]

[0006] There is still a need for sotrasib-containing compositions and sotrasib-containing pharmaceutical compositions that are suitable for patients. [Means for solving the problem]

[0007] This disclosure provides amorphous solid dispersions (ASDs), such as spray-dried dispersions (SDDs), comprising sotrasib and at least one polymer selected from the group consisting of cationic acrylate copolymers, vinylpyrrolidone acetate copolymers, cellulose polymers, and combinations thereof.

[0008] This disclosure also provides a process for producing the disclosed ASD, comprising sotrasib and at least one polymer.

[0009] This disclosure further provides pharmaceutical compositions and methods using the disclosed ASD, comprising sotrasib and at least one polymer. [Brief explanation of the drawing]

[0010] [Figure 1] The XRPD of an amorphous solid dispersion (ASD) containing sotrasib and EPO as described in Example 1 is shown. [Figure 2] The XRPD of an amorphous solid dispersion (ASD) containing sotrasib and PVP-VA as described in Example 1 is shown. [Figure 3] The XRPD of an amorphous solid dispersion (ASD) containing sotrasib and HPMCAS-M as described in Example 1 is shown. [Figure 4] Shows the XRPD of spray-dried sotrasib as described in Example 1. [Figure 5] Shows the results of the dissolution test of the amorphous solid dispersion prepared as described in Example 1 when compared with crystalline sotrasib as a reference. [Figure 6] Shows the biorelevant dissolution of sotrasib (amorphous). [Figure 7] Shows the biorelevant dissolution of sotrasib (crystalline). [Figure 8] Shows the biorelevant dissolution of the ASD containing EPO. [Figure 9] Shows the biorelevant dissolution of the ASD containing PVP-VA. [Figure 10] Shows the biorelevant dissolution of the ASD containing HPMCAS-M. [Figure 11] Shows the comparison of the biorelevant dissolution of amorphous and crystalline sotrasib. [Figure 12] Shows the comparison of the biorelevant dissolution of sotrasib (amorphous and crystalline) and ASD 1-3 over a time period of 0 - 210 minutes. [Figure 13] Shows the comparison of the biorelevant dissolution of sotrasib (amorphous and crystalline) and ASD 1-3 over a time period of 30 - 210 minutes. [Figure 14A] Shows that the dissolution (FaSSIF) of ASD 1-3 at T = 0 (Figure 14A), 1 month (Figure 14B) and 2 months (Figure 14C) was compared with amorphous and crystalline sotrasib. [Figure 14B] Shows that the dissolution (FaSSIF) of ASD 1-3 at T = 0 (Figure 14A), 1 month (Figure 14B) and 2 months (Figure 14C) was compared with amorphous and crystalline sotrasib. [Figure 14C] Shows that the dissolution (FaSSIF) of ASD 1-3 at T = 0 (Figure 14A), 1 month (Figure 14B) and 2 months (Figure 14C) was compared with amorphous and crystalline sotrasib. [Figure 15A] Shows the biorelevant dissolution of ASD 1-3 compared with amorphous and crystalline sotrasib in intestinal fluid and gastric fluid. [Figure 15B]This shows the bio-related solubility of ASD 1-3 in intestinal and gastric juices compared to amorphous and crystalline sotrasib. [Figure 15C] This shows the bio-related solubility of ASD 1-3 in intestinal and gastric juices compared to amorphous and crystalline sotrasib. [Figure 16] Tabletability is expressed as the relative tensile strength against compressive pressure of microcrystalline cellulose (MCC Ph 102), lactose, and ASD 3. [Figure 17] Compression moldability is expressed as the relative tensile strength versus solid content ratio of microcrystalline cellulose (MCC Ph 102), lactose, and ASD 3. [Figure 18] This shows the dissolution of the 4% ASD 3 blend from Example 4. [Figure 19] The dissolution of 71% ASD 3 tablets in Example 4 is shown. [Figure 20] This shows the dissolution of the 94% ASD 3 blend in Example 4. [Modes for carrying out the invention]

[0011] This disclosure provides amorphous solid dispersions (ASDs), such as spray-dried dispersions (SDDs), comprising sotrasib and at least one polymer as described herein. Other ASDs include those obtained by hot-melt extrusion, freeze-drying, rotary evaporation, use of supercritical CO2, or cosolvent precipitation.

[0012] The applicant has found that the ASDs of the present disclosure, comprising sotracib, offer various advantages over conventional formulations. For example, ASDs comprising sotracib and at least one polymer described herein have been found to yield several advantages, such as unexpectedly good solubility, sustained enhancement of solubility, improved ease of formulation, and / or improved bio-dissolution, which may lead to improved in vivo bioavailability. While not wishing to be bound by any particular theory, the ASDs disclosed herein may result in improved bioavailability of sotracib, for example, due to one or more of the following: 1) improved drug dispersibility, thereby preventing or slowing crystallization in the solid state; 2) improved in vivo dissolution, thereby allowing the drug to be released into the gastrointestinal tract; and / or 3) inhibition of precipitation or crystallization of aqueous-soluble drugs. Preferably, the ASDs contain sotracib in an amorphous (i.e., non-crystalline) form in the disclosed compositions.

[0013] ASD can be prepared using spray drying technology. Spray drying is a process that involves breaking down (atomizing) a liquid mixture into small droplets and rapidly removing the solvent from the mixture in a container with a strong driving force for evaporation of the solvent from the droplets. A strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of the solvent in the spray dryer well below the vapor pressure of the solvent at the temperature of the drying droplets. This can be achieved by (1) maintaining the pressure in the spray dryer at a partial vacuum (e.g., 0.01–0.50 atm), (2) mixing the droplets with a heated drying gas, or (3) both. For example, a drug in acetone and a solution of hydroxypropyl methylcellulose acetate succinate (HPMCAS) can be properly spray dried by spraying the solution at a temperature of 50°C (the vapor pressure of acetone at 50°C is about 0.8 atm) into a chamber held at a total pressure of 0.01–0.2 atm by connecting the outlet to a vacuum pump. Alternatively, the acetone solution may be sprayed into a chamber mixed with nitrogen or another inert gas at a temperature of 80–180°C and a pressure of 1.0–1.2 atmospheres. The spray-drying process and apparatus are generally described, for example, in Chemical Engineers' Handbook, Sixth Edition (RHPerry, DW Green, JOMaloney, eds.), McGraw-Hill Book Co., 1984, pages 20–54 to 20–57. Further details regarding the spray-drying process and apparatus are outlined by Marshall ("Atomization and Spray-Drying," Chem.Eng.Prog.Monogr.Series, 50

[1954] 2).

[0014] ASD can be used in the preparation of pharmaceutical compositions using methods known in the art, such as roller compression, fluidized bed agglomeration, or spray coating.

[0015] Sotrasib The disclosed ASD contains sotrasib. Typically, the disclosed ASD contains sotrasib in an amorphous form. In some embodiments, the sotrasib present in the ASD does not contain crystalline sotrasib in any way. As used herein, the term “not contain in any way” means that the amount of crystalline sotrasib is less than 5% by weight of the total amount of sotrasib present (e.g., 5.0% by weight or less, e.g., 4.5% by weight, 4.0% by weight, 3.5% by weight, 3.0% by weight, 2.5% by weight, 2.0% by weight, 1.5% by weight, 1.0% by weight, 0.5% by weight or less). In some embodiments, the disclosed amorphous solid dispersion does not contain any amount of crystalline sotrasib detectable by X-ray powder diffraction (XRPD) when measured by CuKα = 1.54 Å.

[0016] Particle size: The disclosed ASD has a suitable particle size (e.g., particle size distribution). In some embodiments, in conjunction with other embodiments herein, the ASD has a D50 of 3 μm to 30 μm (e.g., 3 to 25 μm, 3 to 20 μm, 3 to 15 μm, 3 to 10 μm, 3 to 7 μm, 4 to 6 μm, 4 to 5 μm, 5 to 30 μm, 5 to 25 μm, 5 to 20 μm, 5 to 15 μm, 5 to 10 μm, 10 to 30 μm, 10 to 25 μm, 10 to 20 μm, 10 to 15 μm, 15 to 30 μm, 15 to 25 μm, 15 to 20 μm, 20 to 30 μm, 20 to 25 μm, or 25 to 30 μm). In some embodiments, in conjunction with other embodiments herein, the ASD has a D50 of 3 μm to 45 μm.

[0017] In some embodiments, in conjunction with other embodiments herein, the ASD has a D10 of 0.7 to 7 μm (e.g., 0.7 to 6 μm, 0.7 to 5 μm, 0.7 to 4 μm, 0.7 to 3 μm, 0.7 to 2 μm, 1 to 2 μm, 3 to 7 μm, 3 to 6 μm, 3 to 5 μm, 3 to 4 μm, 4 to 7 μm, 4 to 6 μm, or 4 to 5 μm). In some embodiments, in conjunction with other embodiments herein, the ASD has a D10 of 0.7 to 15 μm.

[0018] In some embodiments, in conjunction with other embodiments of this specification, the ASD has a D90 of 10-40 μm (e.g., 10-35 μm, 10-30 μm, 10-25 μm, 10-20 μm, 10-15 μm, 11-19 μm, 12-18 μm, 13-17 μm, 14-16 μm, 15-40 μm, 15-35 μm, 15-30 μm, 15-25 μm, 15-20 μm, 20-40 μm, 25-35 μm, 30-35 μm, 25-40 μm, 25-35 μm, 25-30 μm, 30-40 μm, 30-35 μm, or 35-40 μm). In some embodiments, in conjunction with other embodiments of this specification, the ASD has a D90 of 10-97 μm.

[0019] In some embodiments, the disclosed ASD comprises a cationic acrylate copolymer (CACP) and has a D50 of 3 μm to 10 μm (e.g., 3 to 7 μm, 4 to 6 μm). An exemplary CACP is Eudragit® E100, as described herein. In some embodiments, in conjunction with other embodiments herein, the ASD comprising CACP has a D10 of 1 μm to 2 μm. In some embodiments, in conjunction with other embodiments herein, the ASD containing CACP has a D90 of 10 μm to 20 μm (e.g., 11 to 19 μm, 12 to 18 μm, 13 to 17 μm, 14 to 16 μm, or 15 to 20 μm). Alternatively or in addition, the ASD containing CACP may have a D90 of 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, or 20 μm.

[0020] In some embodiments, the disclosed ASD comprises a vinylpyrrolidone acetate copolymer (VAc). An exemplary VAC is Kollidon® VA 64, as described herein. In these embodiments, the ASD comprising VAC typically has a specific particle size distribution, as described herein for CACP.

[0021] In some embodiments, the disclosed ASD comprises a cellulose polymer and has a D50 of 10 μm to 30 μm (e.g., 10 to 25 μm, 15 to 30 μm, or 15 to 20 μm). An exemplary cellulose polymer is hydroxypropyl methylcellulose acetate succinate, as described herein. In some embodiments, in conjunction with other embodiments herein, the ASD comprising a cellulose polymer has a D50 of 10 μm, 15 μm, 20 μm, 25 μm, or 30 μm. In some embodiments, the ASD comprises HPMCAS, as described herein, and has a D50 of 10 μm to 30 μm. In some embodiments, in conjunction with other embodiments herein, the ASD comprising a cellulose polymer (e.g., HPMCAS) has a D10 of 3 μm to 7 μm (e.g., 4 to 6 μm). In some embodiments, in conjunction with other embodiments herein, the ASD comprising a cellulose polymer (e.g., HPMCAS) has a D90 of 30 μm to 40 μm (e.g., 30 to 35 μm, 35 to 40 μm, or 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 μm).

[0022] Quantity: The disclosed ASD contains a suitable amount of sotrasib. If the ASD contains too little sotrasib, the ASD will not have the desired elution properties. In addition, if the ASD contains too much sotrasib, the ASD may be too expensive or suffer other performance problems (e.g., physical instability). In some embodiments, in conjunction with other embodiments herein, the ASD disclosed herein has a weight ratio of sotrasib to polymer of 1:50 to 10:1 (e.g., 1:10 to 1:1). Furthermore, in various embodiments, the weight ratio of sotrasib to polymer in the ASD may be 1:50, 1:45, 1:40, 1:35, 1:30, 1:25, 1:20, 1:15, 1:10, 1:5, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1). In some embodiments, the weight ratio of sotrasib to polymer is 1:4. In some embodiments, the weight ratio of sotrasib to polymer is 1:3.

[0023] In some embodiments, in conjunction with other embodiments herein, sotrasib is present in an amount of 10 to 80% by weight of ASD (e.g., 15 to 75% by weight, 20 to 70% by weight, 20 to 65% by weight, 20 to 60% by weight, 20 to 55% by weight, 20 to 50% by weight, 20 to 45% by weight, 20 to 40% by weight, 20 to 35% by weight, or 20 to 30% by weight of ASD). In some embodiments, sotrasib is 25% by weight of ASD.

[0024] polymer The ASDs disclosed herein comprise one or more polymers as described herein. Preferably, the polymers of the ASD provide a “matrix” capable of solubilizing an active pharmaceutical ingredient (API) (e.g., sotracib) while yielding a desired release profile. Suitable polymers include those selected from the group consisting of cationic acrylate copolymers, vinylpyrrolidone acetate copolymers, cellulose polymers, and combinations thereof. In some embodiments, in conjunction with other embodiments herein, the ASD comprises at least one polymer comprising a random copolymer.

[0025] Cationic acrylate copolymer (CACP) In some embodiments, ASD comprises a cationic acrylate polymer. In various embodiments, CACP comprises a polymethacrylate polymer. In some embodiments, CACP comprises a copolymer based on monomers containing aminoalkyl methacrylate and alkyl methacrylate. Exemplary suitable aminoalkyl methacrylates include, for example, dialkylaminoalkyl methacrylate (e.g., 2-dialkylaminoalkyl methacrylate). Exemplary suitable alkyl methacrylates include butyl methacrylate and methyl methacrylate. In some embodiments, CACP comprises a copolymer based on monomers containing 2-dimethylaminoethyl methacrylate and alkyl methacrylate. In some embodiments, CACP comprises a copolymer based on monomers containing 2-dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

[0026] In some embodiments, in conjunction with other embodiments herein, the cationic acrylate copolymer is based on monomers comprising 2-dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a monomer ratio of 2:1:1. In some embodiments, in conjunction with other embodiments herein, the cationic acrylate copolymer is poly((2-dimethylaminoethyl)methacrylate, butyl methacrylate, methyl methacrylate)(2:1:1).

[0027] An exemplary cationic acrylate polymer is, for example, Eudragit® E100, commercially available from Evonik Industries (Essen, Germany). Eudragit® 100 is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a ratio of 2:1:1, as follows: [ka] Here, the monomers are randomly distributed along the copolymer chain. Eudragit® E100 is commercially available in several forms (e.g., granules, powder and liquid) under various trade names (e.g., Eudragit® E PO and Eudragit® 12,5).

[0028] Vinylpyrrolidone acetate copolymer (VAC) In some embodiments, ASD comprises a vinylpyrrolidone-acetate copolymer. In some embodiments, VAC comprises a monomer-based copolymer comprising an N-vinyllactam monomer and a vinyl acetate monomer. Exemplary N-vinyllactam monomers include N-vinylpyrrolidone and N-vinylcaprolactam. Exemplary suitable vinyl acetate monomers include vinyl acetate, vinyl propionate, vinyl butyrate, and tert-vinyl butyrate. In some embodiments, in conjunction with other embodiments herein, the N-vinyllactam monomer comprises N-vinylpyrrolidone. In some embodiments, in conjunction with other embodiments herein, the acetate monomer comprises vinyl acetate.

[0029] In some embodiments, in conjunction with other embodiments herein, VAC comprises one or more polymers selected from povidone, copovidone, polyvinyl acetate, and combinations thereof.

[0030] In some embodiments, in conjunction with other embodiments herein, the ratio of N-vinyl lactam monomer to acetate monomer is 6:4.

[0031] An example of VAC is Kollidon® VA 64 (e.g., Kollidon® VA 64 or Kollidon® VA 64 Fine), which is commercially available in various forms from BASF (Wyandotte, MI).

[0032] Cellulose polymer In some embodiments, the ASD comprises a cellulose polymer. In some embodiments, in conjunction with other embodiments herein, the cellulose polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose, and combinations thereof. In some embodiments, the cellulose polymer comprises HPMCAS. In some embodiments, the cellulose polymer is HPMCAS.

[0033] As used herein, HPMCAS refers to a family of cellulose derivatives that may have (1) two types of ether substituents, methyl and / or 2-hydroxypropyl, and (2) two types of ester substituents, acetyl and / or succinyl. HPMCAS is also known by the chemical name O-(2-hydroxypropyl)-O-methylcellulose acetate succinate. The degree of substitution of each of the four common types described herein can be varied over a wide range to affect the chemical and physical properties of the polymer. This versatility of HPMCAS makes it possible to optimize its structure to obtain good performance with specific drugs of interest. HPMCAS can be synthesized or commercially available. Three examples of commercially available HPMCAS include Shin-Etsu AQOAT®-LF, Shin-Etsu AQOAT®-MF, and Shin-Etsu AQOAT®-HF (Shin-Etsu Chemical Co., Ltd.), where the L, M, and H grades refer to the pH at which the polymer dissolves (L = low pH ≥ 5.5, M = medium pH ≥ 6.0, and H = high pH ≥ 6.5). In some embodiments, the HPMCAS is L grade (e.g., HPMCAS-LF, or HPMCAS-LG, or HPMCAS-LMP). The F, G, and MP grades refer to different average particle sizes (F is a fine powder with a D50 of ≤ 10 μm, MP is a medium particle size with a D50 of 70-300 μm, and G is a free-flowing granule with a median particle size typically of about 1000 μm). Grade L contains 20-24%, 5-9%, 5-9%, and 14-18% of methoxy%, hydroxypropoxy%, acetyl%, and succinoyl%, respectively. Grade M contains 21-25%, 5-9%, 7-11%, and 10-14% of methoxy%, hydroxypropoxy%, acetyl%, and succinoyl%, respectively. Grade H contains 22-26%, 6-10%, 10-14%, and 4-8% of methoxy%, hydroxypropoxy%, acetyl%, and succinoyl%, respectively.

[0034] HPMCAS has any suitable molecular weight. In some embodiments, the average weight-average molecular weight range of HPMCAS is 10,000 to 1,000,000 daltons (e.g., 10,000 to 400,000 daltons or 55,000 to 115,000 daltons, when determined using polyethylene oxide standards). Note that molecular weight may be expressed herein as daltons (Da) or g / mol, and these are used interchangeably throughout. The molecular weight range may also vary based on the degree of substitution (e.g., the amount of acetyl and / or succinyl groups present). For example, in various embodiments, in conjunction with other embodiments above or below, the average weight-average molecular weight of HPMCAS is about 15,000 to 20,000 daltons, e.g., 15,000, 16,000, 17,000, 18,000, 19,000 or 20,000 daltons. In some embodiments, the average weight-average molecular weight of HPMCAS is 17,700, 17,900, 18,800, 18,900, 20,400, or 21,200 daltons. In some embodiments, along with other embodiments described above or below, the number-average molecular weight is approximately 13,000 daltons.

[0035] process This disclosure further provides processes for preparing the ASDs disclosed herein. As described above, ASDs can be prepared by spray drying, hot melt extrusion, freeze-drying, rotary evaporation, use of supercritical CO2, or cosolvent precipitation.

[0036] In some embodiments, the Disclosure provides a process for producing an ASD, which comprises (a) mixing an amorphous sotrasib with one or more polymers and a solvent to form a solution, and (b) spray-drying the solution from step (a) to obtain a spray-dried dispersion. Exemplary processes are described in the Examples.

[0037] In some embodiments, in conjunction with other embodiments herein, polymer solutions prepared according to the disclosed processes include cationic acrylate copolymers, vinylpyrrolidone acetate copolymers, cellulose polymers, and combinations thereof, as described herein.

[0038] In some embodiments, in conjunction with other embodiments herein, the disclosed process includes mixing sotrasib and polymer in a weight ratio of 1:50 to 10:1 (e.g., 1:10 to 1:1) as described herein, i.e., 1:50, 1:45, 1:40, 1:35, 1:30, 1:25, 1:20, 1:15, 1:10, 1:5, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1). In some embodiments, the weight ratio of sotrasib to polymer is 1:4. In some embodiments, the weight ratio of sotrasib to polymer is 1:3.

[0039] solvent The disclosed methods are carried out in a suitable solvent. In some embodiments, the solvent is a polar aprotic solvent, such as acetone, acetonitrile, dichloromethane, dimethylformamide (DMF), dimethylpropylene urea, dimethyl sulfoxide (DMSO), ethyl acetate, hexamethyl phosphate triamide, or tetrahydrofuran (THF). In some embodiments, the solvent is a polar protic solvent, such as formic acid, n-butanol, isopropanol, nitromethane, ethanol, methanol, acetic acid, or water. In some embodiments, the solvent is a polar aprotic solvent, a polar protic solvent, or a combination thereof. In some embodiments, together with other embodiments described above or below, the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, cyclopentyl methyl ether, ethyl acetate, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether, N-methylpyrrolidone, dimethyl sulfoxide, dimethylformamide, toluene, n-heptane, and combinations thereof. In some embodiments, the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetic acid, acetone, acetonitrile, dichloromethane, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and combinations thereof. In some embodiments, the solvent is acetone, dichloromethane, or a mixture thereof.

[0040] The solvent is present in a suitable amount. If the amount of solvent present is too small, the reactants may not mix in a suitable manner to facilitate the reaction or processing of the reaction mixture. Conversely, if the amount of solvent is too large, the concentration of the reactants may be too dilute for a suitable reaction, or the processing of the reaction may become unnecessarily complicated, or the energy required to remove the solvent may become too high.

[0041] In various embodiments, this disclosure provides an ASD prepared according to the disclosed process.

[0042] Pharmaceutical composition In some embodiments, the disclosed ASD is administered in the form of a pharmaceutical composition. In these embodiments, the pharmaceutical composition comprises the ASD and a pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipients include, for example, vehicles, adjuvants, and diluents, which are well known to those skilled in the art and readily available. Typically, a pharmaceutically acceptable excipient is chemically inert to the active compound and has no harmful side effects or toxicity under the conditions of use. In some embodiments, in conjunction with other embodiments herein, the pharmaceutically acceptable excipient is a diluent, a disintegrant, a lubricant, or a combination thereof.

[0043] In some embodiments, the disclosed pharmaceutical compositions include a disintegrant. Exemplary disintegrants include, but are not limited to, cross-linked sodium carboxymethylcellulose (croscarmellose sodium), cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, pregelatinized starch, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, and aluminum magnesium silicate, and combinations thereof. In some embodiments, the disintegrant includes croscarmellose sodium or sodium starch glycolate, or both. The disintegrant may include croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, aluminum magnesium silicate, or combinations thereof. In some embodiments, the disintegrant includes croscarmellose sodium, sodium starch glycolate, or combinations thereof. In some embodiments, the disintegrant is croscarmellose sodium.

[0044] In some embodiments, the disclosed pharmaceutical composition includes a diluent. In some embodiments, the diluent includes lactose, dibasic calcium phosphate (DCP), mannitol, sorbitol, xylitol, calcium carbonate, magnesium carbonate, tribasic calcium phosphate, trehalose, microcrystalline cellulose, starch, or a combination thereof. In some embodiments, the diluent includes lactose, dibasic calcium phosphate (DCP), mannitol, microcrystalline cellulose, starch, or a combination thereof. In some embodiments, the diluent includes lactose, microcrystalline cellulose, or a combination thereof. In some embodiments, the diluent includes lactose, starch, and a combination thereof. In some embodiments, the starch is pregelatinized starch or corn starch. In some embodiments, the diluent includes lactose, dibasic calcium phosphate (DCP), mannitol, or a combination thereof. In some embodiments, lactose is lactose monohydrate.

[0045] In some embodiments, the disclosed pharmaceutical composition includes a lubricant. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, oleic acid, caprylic acid, stearic acid, magnesium isovalerate, calcium laurate, magnesium palmitate, behenic acid, glyceryl behenate, glyceryl stearate, sodium stearyl fumarate, potassium stearyl fumarate, zinc stearate, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, talc, polyethylene glycol, and hydrogenated vegetable oils. In some embodiments, the lubricant is magnesium stearate. In some embodiments, in conjunction with other embodiments herein, the lubricant includes magnesium stearate, calcium stearate, oleic acid, caprylic acid, stearic acid, magnesium isovalerate, calcium laurate, magnesium palmitate, behenic acid, glyceryl behenate, glyceryl stearate, sodium stearyl fumarate, potassium stearyl fumarate, zinc stearate, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, talc, polyethylene glycol, hydrogenated vegetable oil, or a combination thereof.

[0046] The disclosed pharmaceutical compositions may be administered in various forms, including, for example, tablets, capsules, granules, powders, solutions, suspensions, and emulsions. The dosage form of the composition may be adjusted to suit the desired mode of administration. For oral administration, the composition may take the form of, for example, tablets or capsules (including softgel capsules), or may be, for example, aqueous or non-aqueous solutions, suspensions, or syrups. Tablets and capsules for oral administration may contain one or more excipients, diluents, and carriers as described herein. Flavoring agents, coloring agents, and / or sweeteners may be added to solid and liquid formulations as needed. Other optional components for oral formulations include, but are not limited to, preservatives, suspending agents, and thickeners. Oral formulations may also have an enteric coating to protect ASD from the acidic environment of the stomach.

[0047] How to use In some embodiments, this disclosure provides methods for treating cancer using the pharmaceutical compositions disclosed herein. In some embodiments, one or more cells of the cancer express the KRAS G12C mutant protein, i.e., the cancer is mediated by the KRAS G12C mutation. Representative cancers that can be treated as described herein include, for example, non-small cell lung cancer, small intestine cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell carcinoma, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, brain cancer, or melanoma. In some embodiments, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, cancer of unknown primary origin, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, or melanoma. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is one or more brain metastases resulting from a primary cancer, such as non-small cell lung cancer. In some embodiments, the cancer is locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation, as determined by a preferred test, such as a test approved by the U.S. Food and Drug Administration (FDA), in which the patient has received at least one prior systemic therapy. In some embodiments, the patient is an adult.

[0048] In some embodiments, the present disclosure provides a method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective dose of sotrasib, provided in the form of an ASD disclosed herein or as a pharmaceutical composition as disclosed herein.

[0049] Embodiment 1. An amorphous solid dispersion (ASD) comprising sotracib and at least one polymer selected from the group consisting of cationic acrylate copolymers, vinylpyrrolidone acetate copolymers, cellulose polymers, and combinations thereof. 2. The ASD according to Embodiment 1, wherein the sotrasib is essentially free of crystalline sotrasib. 3. The ASD according to Embodiment 1 or 2, which is free from crystalline sotrabe in amounts detectable by XRPD. 4. An ASD according to any one of Embodiments 1 to 3, wherein at least one polymer comprises a cationic acrylate copolymer. 5. The ASD according to Embodiment 4, wherein the cationic acrylate copolymer comprises a polymethacrylate polymer. 6. The cationic acrylate copolymer comprises a copolymer based on monomers including aminoalkyl methacrylate and alkyl methacrylate, as described in any one of Embodiments 1 to 5. 7. The ASD according to any one of Embodiments 1 to 6, wherein the cationic acrylate copolymer comprises a copolymer based on monomers including 2-dimethylaminoethyl methacrylate and alkyl methacrylate. 8. The ASD according to any one of Embodiments 1 to 7, wherein the cationic acrylate copolymer comprises a copolymer based on monomers including 2-dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. 9. The ASD according to Embodiment 8, wherein the cationic acrylate copolymer is based on a monomer comprising 2-dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a monomer ratio of 2:1:1. 10. The ASD according to any one of Embodiments 1 to 9, wherein the cationic acrylate copolymer is poly((2-dimethylaminoethyl) methacrylate, butyl methacrylate, methyl methacrylate) (2:1:1). 11. The vinylpyrrolidone-acetate copolymer comprises a monomer-based copolymer containing an N-vinyllactam monomer and a vinyl acetate monomer, as described in any one of Embodiments 1 to 10. 12. The ASD according to Embodiment 11, wherein the N-vinyllactam monomer comprises N-vinylpyrrolidone. 13. The acetate monomer comprises vinyl acetate, as described in Embodiment 11 or 12. 14. The ASD according to any one of Embodiments 11 to 13, wherein the polymer comprises one or more polymers selected from povidone, copovidone, polyvinyl acetate and combinations thereof. 15. The ASD according to any one of Embodiments 11 to 14, wherein the ratio of N-vinyl lactam monomer to acetate monomer is 6:4. 16. An ASD according to any one of Embodiments 1 to 22, wherein at least one polymer comprises a random copolymer. 17. An ASD according to any one of Embodiments 1 to 23, wherein at least one polymer comprises one or more cellulose polymers selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose, and combinations thereof. 18. The cellulose polymer comprises hydroxypropyl methylcellulose acetate succinate, as described in Embodiment 24. An ASD according to any one of Embodiments 1 to 16, having a D50 of 19.3 μm to 10 μm. 20. D50 is 3 μm to 7 μm, as described in Embodiment 19. 21. D50 is 4 μm to 6 μm, as described in Embodiment 20. An ASD according to any one of embodiments 19 to 21, having a D10 of 22.1 μm to 2 μm. An ASD according to any one of embodiments 19 to 22, having a D90 of 23.10 μm to 20 μm. ASD according to embodiment 17 or 18, having a D50 of 24.10 μm to 30 μm. The ASD according to Embodiment 24, having a D50 of 25.15 μm to 20 μm. ASD according to embodiment 24 or 25, having a D10 of 26.3 μm to 7 μm. The ASD according to Embodiment 26, having a D90 of 27.30 μm to 40 μm. Further provided herein as an alternative embodiment 27 is the ASD according to Embodiment 26, having a D90 of 30 μm to 50 μm. An ASD according to any one of Embodiments 1 to 27, having a weight ratio of sotrasib to polymer of 28.1:50 to 10:1. 29. The ASD according to Embodiment 28, wherein the weight ratio of sotrasib to polymer is 1:10 to 1:1. 30. The ASD according to Embodiment 29, wherein the weight ratio of sotrasib to polymer is 1:4. Further provided herein as an alternative embodiment 30 is the ASD according to Embodiment 29, wherein the weight ratio of sotrasib to polymer is 1:3. 31. Sotrasib is 10 to 80% by weight of ASD, as described in any one of Embodiments 1 to 30. 32. The ASD according to Embodiment 31, wherein the sotrasib is 25% by weight of the ASD. 33. A process for producing amorphous drug dispersions (ASDs), (a) Mixing amorphous sotrasib with one or more polymers and a solvent to form a solution, (b) spray-dry the solution from step (a) to obtain ASD A process including the above. As an alternative embodiment 33, further provided herein is a process for producing an amorphous drug dispersion (ASD), (a) Mixing sotrasib with one or more polymers and a solvent to form a solution, (b) spray-dry the solution from step (a) to obtain ASD This process includes [something]. 34. The process according to Embodiment 33, wherein the solvent comprises acetone, dichloromethane, or a mixture thereof. 35. The process according to Embodiment 33 or 34, wherein one or more polymers are selected from the group consisting of cationic acrylate copolymers, vinylpyrrolidone acetate copolymers, cellulose polymers, and combinations thereof. 36. The process according to any one of embodiments 33 to 35, wherein the sotrasib and polymer are present in a weight ratio of 1:50 to 10:1. 37. The process according to Embodiment 36, wherein the weight ratio of sotrasib to polymer is 1:10 to 1:1. 38. The process according to Embodiment 37, wherein the weight ratio of sotrasib to polymer is 1:4. Further provided herein as an alternative embodiment 38 is the process according to Embodiment 37, wherein the weight ratio of sotrasib to polymer is 1:4. 39. The process according to any one of embodiments 33 to 38, wherein the ASD comprises 10 to 80% by weight of sotrasib. 40. The process according to Embodiment 39, wherein ASD comprises 15-50% by weight of sotrasib. 41. The process according to Embodiment 40, wherein the ASD comprises a sotrasib in an amount of 25% by weight of ASD. 42. ASD prepared by the process described in any one of Embodiments 33 to 41. 43. The ASD according to Embodiment 42, which is essentially free of crystalline sotrasib. 44. The ASD according to Embodiment 42, which is free from crystalline sotrabe in amounts detectable by XRPD. 45. A pharmaceutical composition comprising an ASD described in any one of embodiments 1 to 32 and 42 to 44, and a pharmaceutically acceptable excipient. 46. ​​The pharmaceutical composition according to Embodiment 45, wherein the pharmaceutically acceptable excipients are diluents, disintegrants, lubricants, or combinations thereof. 47. The pharmaceutical composition according to Embodiment 46, wherein the diluent comprises lactose, dibasic calcium phosphate (DCP), mannitol, sorbitol, xylitol, calcium carbonate, magnesium carbonate, tribasic calcium phosphate, trehalose, microcrystalline cellulose, starch, or a combination thereof. 48. The pharmaceutical composition according to Embodiment 47, wherein the diluent comprises lactose, dibasic calcium phosphate (DCP), mannitol, microcrystalline cellulose, starch, or a combination thereof. 49. The pharmaceutical composition according to Embodiment 48, wherein the diluent comprises lactose, microcrystalline cellulose, or a combination thereof. 50. The pharmaceutical composition according to Embodiment 48, wherein the diluent comprises lactose, starch, and combinations thereof. 51. The pharmaceutical composition according to Embodiment 48, wherein the starch is pregelatinized starch or corn starch. 52. The pharmaceutical composition according to Embodiment 48, wherein the diluent comprises lactose, dibasic calcium phosphate (DCP), mannitol, or a combination thereof. 53. The pharmaceutical composition according to any one of Embodiments 47 to 52, wherein lactose is lactose monohydrate. 54. A pharmaceutical composition according to any one of Embodiments 46 to 53, wherein the disintegrant comprises cross-linked sodium carboxymethylcellulose (croscarmellose sodium), cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, pregelatinized starch, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, and magnesium aluminum silicate, or a combination thereof. 55. The pharmaceutical composition according to Embodiment 54, wherein the disintegrant comprises croscarmellose sodium, sodium starch glycolate, or a combination thereof. 56. The pharmaceutical composition according to Embodiment 54, wherein the disintegrant is croscarmellose sodium. 57. A pharmaceutical composition according to any one of Embodiments 46 to 56, wherein the lubricant comprises magnesium stearate, calcium stearate, oleic acid, caprylic acid, stearic acid, magnesium isovalerate, calcium laurate, magnesium palmitate, behenic acid, glyceryl behenate, glyceryl stearate, sodium stearyl fumarate, potassium stearyl fumarate, zinc stearate, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, talc, polyethylene glycol, hydrogenated vegetable oil, or a mixture thereof. 58. The pharmaceutical composition according to Embodiment 57, wherein the lubricant is magnesium stearate. 59. A method for treating cancer in a patient, comprising administering to the patient a therapeutically effective dose of sotrasib, provided as an ASD according to any one of Embodiments 1-32 and 42-44 or as a pharmaceutical composition according to any one of Embodiments 45-58. 60. The method according to Embodiment 59, wherein one or more cancer cells express the KRAS G12C mutant protein. 61. The method according to Embodiment 59 or 60, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, cancer of unknown primary origin, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, or melanoma. 62. A pharmaceutical composition comprising an ASD described in any one of embodiments 1 to 32 and 42 to 44, and a pharmaceutically acceptable excipient. 63. The pharmaceutical composition according to Embodiment 62, comprising a disintegrant. 64. The pharmaceutical composition according to Embodiment 63, wherein the disintegrant comprises cross-linked sodium carboxymethylcellulose (croscarmellose sodium), cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, pregelatinized starch, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, and magnesium aluminum silicate, or a combination thereof. 65. The pharmaceutical composition according to Embodiment 64, wherein the disintegrant comprises croscarmellose sodium, sodium starch glycolate, or a combination thereof. 66. The pharmaceutical composition according to Embodiment 65, wherein the disintegrant is croscarmellose sodium. 67. The pharmaceutical composition is the pharmaceutical composition according to any one of embodiments 63 to 66, comprising 2 to 10% (w / w) of a disintegrant. A pharmaceutical composition according to any one of embodiments 63 to 66, comprising 68.6% (w / w) of a disintegrant and 94% (w / w) of ASD. The pharmaceutical composition according to Embodiment 67, comprising 69.3% (w / w), 3.5% (w / w), or 6% (w / w) of a disintegrant. 70. A pharmaceutical composition according to any one of embodiments 62 to 67 and 69, comprising a diluent. 71. The pharmaceutical composition according to Embodiment 70, wherein the diluent comprises lactose, dibasic calcium phosphate (DCP), mannitol, sorbitol, xylitol, calcium carbonate, magnesium carbonate, tribasic calcium phosphate, trehalose, microcrystalline cellulose, starch, or a combination thereof. 72. The pharmaceutical composition according to Embodiment 71, wherein the diluent comprises lactose, dibasic calcium phosphate (DCP), mannitol, microcrystalline cellulose, starch, or a combination thereof. 73. The pharmaceutical composition according to Embodiment 72, wherein the diluent comprises lactose, microcrystalline cellulose, or a combination thereof. A pharmaceutical composition according to any one of embodiments 70 to 73, comprising a diluent in an amount of 74.1 to 95% (w / w). The pharmaceutical composition according to Embodiment 74, comprising a 75.92% (w / w) or 25% (w / w) diluent. A pharmaceutical composition according to any one of embodiments 70 to 75, comprising 76.25% (w / w) lactose. A pharmaceutical composition according to any one of Embodiments 70 to 75, comprising 77.23% (w / w) lactose and 69% (w / w) microcrystalline cellulose. 78. A pharmaceutical composition according to any one of embodiments 62-67 and 69-77, comprising a lubricant. 79. The pharmaceutical composition according to Embodiment 78, wherein the lubricant comprises magnesium stearate, calcium stearate, oleic acid, caprylic acid, stearic acid, magnesium isovalerate, calcium laurate, magnesium palmitate, behenic acid, glyceryl behenate, glyceryl stearate, sodium stearyl fumarate, potassium stearyl fumarate, zinc stearate, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, talc, polyethylene glycol, hydrogenated vegetable oil, or a combination thereof. 80. The pharmaceutical composition according to Embodiment 78, wherein the lubricant is magnesium stearate. A pharmaceutical composition according to any one of Embodiments 78 to 80, comprising 81.0.5-5% (w / w) of a lubricant. The pharmaceutical composition according to Embodiment 81, comprising 82.0.6% (w / w) or 1% (w / w) of a lubricant. The pharmaceutical composition according to Embodiment 62, comprising 83.94% (w / w) ASD 3 and 6% (w / w) croscarmellose sodium. The pharmaceutical composition according to Embodiment 62, comprising 84.70.7% (w / w) ASD 3, 25.2% (w / w) lactose, 3.5% (w / w) croscarmellose sodium, and 0.6% (w / w) magnesium stearate. The pharmaceutical composition according to Embodiment 62, comprising 85.4% (w / w) ASD 3, 69% (w / w) microcrystalline cellulose, 23% (w / w) lactose, 3% (w / w) croscarmellose sodium, and 1% (w / w) magnesium stearate. 86. A method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of sotrasib provided as an ASD according to any one of Embodiments 1 to 32 and 42 to 44 or as a pharmaceutical composition according to any one of Embodiments 62 to 85. 87. The method according to embodiment 86, wherein one or more cancer cells express the KRAS G12C mutant protein. 88. The method according to Embodiment 86 or 87, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, cancer of unknown primary origin, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, or melanoma. 89. The method according to embodiment 88, wherein the cancer is non-small cell lung cancer. 90. The method according to embodiment 88, wherein the cancer is colorectal cancer. 91. The method according to Embodiment 88, wherein the cancer is pancreatic cancer. [Examples]

[0050] The following embodiments illustrate the disclosed processes further, but should not be interpreted as limiting their scope.

[0051] In this specification, the following abbreviations are used: SL / M refers to standard liters / min, FaSSIF refers to simulated intestinal fluid under fasting conditions, FaSSGF refers to gastric fluid under fasting conditions, HPLC refers to high-performance liquid chromatography, SDD refers to spray-dried dispersion, DAD refers to diode array detector, HPMCAS refers to hydroxypropyl methylcellulose acetyl succinate, XRPD refers to X-ray powder diffraction, DSC refers to differential scanning calorimetry, Tg refers to glass transition temperature, TGA refers to thermogravimetric analysis, and PSD refers to particle size distribution.

[0052] Example 1 - Preparation of a solid dispersion containing sotracib Solid dispersions containing sotracib were prepared using Eudragit® E PO, polyvinylpyrrolidone / vinyl acetate (PVP-VA), and HPMCAS-M under a 25% drug load. These samples were characterized as amorphous by XRPD, and their glass transition temperatures were measured by differential scanning. The dispersions were prepared using the following spray-drying procedure.

[0053] General procedure for spray drying: The following is an exemplary procedure for preparing a spray-dried sample using Buchi 290 (Buchi Corporation, New Castle, Delaware).

[0054] Assembly: (a) A solution of 1.25 g of sotrasib and (b) a solution of 3.75 g of polymer are prepared together in 100 mL of solvent (e.g., dichloromethane or 1:1 dichloromethane:acetone). Table 1 below shows three ASDs prepared using different polymers with sotrasib via this procedure. Connect the drying chamber with an O-ring, point the outlet towards the cyclone, and secure it from the left side using the black handle. Connect the recovery container. Connect the chamber to the cyclone through the metal connector with the temperature probe port. Connect and secure the Cyclone top outlet with the white plastic connector. Connect to the cooler. Insert the nozzle into the top of the drying chamber, connect the N2 flow with a screw (red tag), and connect the cooling tube (left side, WK 230 Lauda Brinkmann). • Secure the syringe containing the solution / solvent.

[0055] operation: • Turn on the cooler, air (left side, blue line on the right), and N2 (right side). If the system is assembled correctly, the oxygen level on the red monitor on the left should be less than 1%. The red light will turn green. Turn on the spray dryer and set the N2 to approximately 0.5% (right side, back, right knob). Parameters for sotrasib spray drying • Use the front knob to set N2 to 8-10 SL / M • Inlet temperature: 70-90°C (on). Track the outlet temperature. ·Outlet temperature: 60~70℃ • Acetone / dichloromethane solution (approximately 5 mL): Manual injection • Spray solution (approx. 100 mL): 1-1.5 mL / min ·Suction device: 100% • Needle size: 1-2mm • Nozzle size: 1.5~2.8mm Secondary drying (SD) Before collecting the collection container, turn off the nitrogen, then turn off the suction device. • Loosely cover the container with aluminum foil and place it in a vac oven at 60°C and 150 mBar overnight.

[0056] [Table 1]

[0057] The results of the XRPD analysis of ASDs in Table 1 are shown in Figures 1-4 (XRPD). The XRPD and DSC results demonstrate that the components of each dispersion were amorphous, i.e., no crystalline substances could be detected by XRPD. Furthermore, the DSC analysis demonstrated that the glass transition temperature (Tg) for each composition was greater than 100°C. For example, the measured Tg for ASD 1 was 57°C and 123°C, while that for ASDs 2 and 3 was 120°C.

[0058] Differential Scanning Calorimetry (DSC) Analysis: DSC data was collected using a TA Instruments Q1000 DSC. Approximately 2–6 mg of sample was placed in a Tzero aluminum pan, sealed with a Tzero lid, and equilibrated at 4°C for 5 minutes. Under a nitrogen purge of approximately 50 mL / min, the temperature was adjusted by ±2°C every 60 seconds while scanning at a rate of approximately 4°C / min from approximately 4°C to 220°C.

[0059] X-ray powder diffraction (XRPD) analysis: XRPD data was obtained using a Bruker D8 Advance diffractometer. Using CuKα rays (1.54 Å), the sample was scanned in continuous mode from 3° to 40° (2θ) with a step size of 0.02° at 40kV and 40mA at ambient temperature (25°C). The incident beam path was equipped with a 2.5° primary solar slit and a 0.6 mm divergent slit in fixed slit mode. The sample was prepared on a low-background sample holder and placed on a rotating stage at a rotation time of 10 revolutions per minute.

[0060] Particle size distribution (PSD): Analysis of each sample was performed using a Sympatec Helos laser diffraction analyzer. The results of the particle size analysis are shown in Table 1 (D10, D50, and D90 values).

[0061] As shown in the following micro-dissolution experiment, in which dissolved substances were quantified by HPLC, all ASDs showed increased solubility and dissolution in FASSIF compared to crystalline sotrasib.

[0062] Dissolution: The dissolution properties of spray-dried sotrasib ASD 1-3 and the control were evaluated as described herein. 2.5 mg of amorphous sotrasib (control) and 10 mg of ASD 1-3 listed in Table 1 were added to separate 10 mL vials of FASSIF (pH 6.50), and samples were collected at 5, 10, 15, 20, 30, 60, and 120 minutes. Each sample was diluted 5-fold in acetonitrile and subjected to HPLC using a C18 column as the stationary phase under the conditions shown in Table 2. The mobile phase was water containing 0.1% trifluoroacetic acid and acetonitrile. This method used a wavelength of 254 nm for detection and quantification, and the gradient was from 5% acetonitrile 95% water to 98% acetonitrile 2% water over 15 minutes.

[0063] [Table 2]

[0064] The dissolution of ASD 1-3 was compared with amorphous and crystalline sotracib (AMG510) (Form I, see International Publication No. 2020 / 236947). The results of the dissolution test are shown in Figure 5, demonstrating that each of the prepared ASDs showed improved dissolution and solubility compared to crystalline sotracib, and that the ASD containing sotracib and HPMCAS-M showed the highest dissolution.

[0065] Bio-mediated solubility: Using amorphous and crystalline sotrasib as reference, the bio-mediated solubility of ASD 1-3 in intestinal and gastric fluids was evaluated as shown in Figures 6-10 (Figures 6 and 7, respectively). A comparison of the bio-mediated solubility of amorphous and crystalline sotrasib is shown in Figure 11. Bio-mediated solubility data was obtained for 30 minutes in simulated fasting gastric fluid (FaSSGF) using a Pion micro-solubility device, and then the samples were transferred to simulated fasting intestinal fluid (FaSSIF) for a further 3 hours while monitoring at a fixed wavelength (355 nm). The bio-mediated solubility of ASD 1-3 is shown in Figures 8-10. A comparison of all bio-mediated solubility is shown in Figure 12 (times 0 to 210 minutes) and Figure 13 (times 30 to 210 minutes). ASD 1 (Figure 8) and 3 (Figure 10) maintained higher sotrasib solubility after transfer to intestinal fluid (Figures 12 and 13).

[0066] Example 2 - Stability testing of ASD 1, ASD 2, and ASD 3 The stability tests for the three ASDs prepared in Example 1 were performed over a period of two months (T=0, 1 month, and 2 months) using XRPD, TGA, DSC, PSD, and dissolution tests (FaSSIF and biocompatible media).

[0067] method Stability testing: ASD samples were stored in low-density polyethylene (LPDE) bags placed in heat-sealed aluminum foil pouches with a desiccant. The foil pouches were then placed in a stabilization chamber at 25°C / 60%RH and removed at specific time points for stability testing (XRPD, TGA, DSC, PSD, lysis, and bio-related lysis).

[0068] X-ray powder diffraction (XRPD) analysis: XRPD data was obtained using a Panalytical PW3040-PRO diffractometer. Using CuKα rays (1.54 Å), the sample was scanned in continuous mode from 3 degrees to 45 degrees (2θ) at room temperature (25°C) with a step size of 0.03 degrees at 45 kV and 40 mA. The incident beam path was equipped with a primary solar slit of 0.04 rad and a divergent slit of 0.38 mm in fixed slit mode. The sample was prepared in a low-background sample holder and placed on the rotating stage with a rotation time of 4 seconds.

[0069] Thermogravimetric Analysis (TGA): TGA was performed to evaluate the presence of residual solvent and any thermal transitions that could lead to weight loss. TGA was performed on a TA Instruments Discovery 550 Series analyzer in a platinum pan at a rate of 25 ml / min under dry nitrogen at 5°C / min up to an ambient temperature of ~200°C. Sample size was approximately 2–8 mg.

[0070] Differential Scanning Calorimetry (DSC) Analysis: DSC data was collected using a TA Instruments Q2500 DSC. Approximately 2-6 mg of the sample was placed in a Tzero aluminum pan and sealed with a Tzero lid. The method log consisted of equilibration to -20°C, isothermal hold for 1.00 minute, heating to 160.0°C at 10.00°C / min, isothermal hold for 1.00 minute, temperature decrease to -20.00°C at 10.00°C / min, isothermal hold for 1.00 minute, heating to 200°C at 10.00°C / min, and marking of cycle completion. The conditions were under nitrogen purging of approximately 50 mL / min.

[0071] Particle size distribution (PSD): Analysis of each sample was performed using a Sympatec Helos laser diffraction analyzer. The results are shown below (D10, D50, and D90 values).

[0072] Dissolution (FaSSIF): The dissolution properties of spray-dried sotrasib ASD 1-3 and the control were evaluated as described herein. 5 mg of amorphous sotrasib (control), 5 mg of crystalline sotrasib (control), and 20 mg of ASD 1-3 were added to separate 20 mL vials of FaSSIF (pH 6.50), and samples were collected at 5, 15, 20, 30, 60, 120, and 180 minutes. All crystalline and amorphous samples were not diluted at the first two time points due to their low solubility, while the remaining three ASDs were diluted 5-fold with 50:50 water:acetonitrile and subjected to HPLC using a C18 column as the stationary phase under the conditions shown in Table 2. The mobile phases were A: water containing 0.1% trifluoroacetic acid and B: acetonitrile containing 0.1% trifluoroacetic acid. This method used a wavelength of 254 nm for detection and quantification, and involved a reverse gradient from 5%B 95%A to 98%B 2%A over 15 minutes.

[0073] Dissolution (Bio-related): The dissolution properties of spray-dried sotrasib ASD 1-3 and the control were evaluated as described herein. 10 mg of amorphous sotrasib (control), 10 mg of crystalline sotrasib (control), and 40 mg of ASD 1-3, listed in Table 1, were added to separate 20 mL vials of FASSIF (pH 6.50), and samples were collected at 5, 10, 20, 30, 35, 40, 50, 60, 90, 120, 150, 180, and 210 minutes. Crystalline samples from 5 to 90 minutes were diluted 10-fold, samples from 120 to 210 minutes were diluted 5-fold, and amorphous samples and the three ASDs were diluted 10-fold in 50:50 water:acetonitrile. HPLC was performed using a C18 column as the stationary phase under the conditions shown in Table 2. Mobile phase A: water containing 0.1% trifluoroacetic acid and B: acetonitrile containing 0.1% trifluoroacetic acid. The method was a reverse gradient from 5%B 95%A to 98%B 2%A over 15 minutes, using a wavelength of 254 nm for detection and quantification.

[0074] result The following results were obtained for the control (amorphous sotracib) and ASD 1-3.

[0075] [Table 3]

[0076] Table 3 shows that ASD 1-3 remains amorphous for at least two months.

[0077] [Table 4]

[0078] Table 4 shows that ASD 1–3 does not show any associated weight changes over a period of at least two months.

[0079] [Table 5]

[0080] Table 5 shows that ASD 1-3 does not show any relevant changes in Tg over a period of at least two months.

[0081] [Table 6]

[0082] Table 6 shows that ASD 1–3 do not show any relevant changes in particle size distribution over a period of at least two months.

[0083] The dissolution of ASD 1-3 was compared with amorphous and crystalline sotrasib (AMG510) (Form I, see International Publication No. 2020 / 236947) at T=0, 1 month, and 2 months. The results of the dissolution tests are shown in Figure 14, demonstrating that each of the prepared ASDs showed accelerated dissolution and solubility compared to crystalline sotrasib over the test period, with ASDs containing sotrasib and HPMCAS-M exhibiting the highest solubility.

[0084] As shown in Figure 15, the bio-related solubility of ASD 1-3 in intestinal and gastric fluid was compared with amorphous and crystalline sotracib (Morph I, see International Publication No. 2020 / 236947). The solubility test results show that each of the prepared ASDs maintained higher sotracib solubility after being transferred to intestinal fluid over the test period.

[0085] Compression moldability and tablet properties were evaluated using ASD 3 (based on HPMCAS-M) as shown in Example 3.

[0086] Example 3 - Compression moldability and tableting properties To guide the preparation of pharmaceutical compositions such as tablets, the compactability and tableting profile of ASD 3 were evaluated.

[0087] The tableting profile describes the relationship between pressure and tablet strength. Compression tests were performed using a Huxley Bertram HB100 compression simulator. This simulator was equipped with 6.35 mm Type B upper and lower punches with rounded flat surfaces. For this evaluation, ASD 3 was first compressed at a compression pressure of 50 MPa using a 6.35 mm die. The amount of compressed material for each data point was approximately 86–95 mg. The punch gap was manually adjusted by adjusting the lower punch to accommodate the powder in the die as needed. Solids content, compression pressure, and relative tensile strength were calculated according to common practice. The data were compared with lactose and microcrystalline cellulose (MCC) 102 produced as described in Example 5 of International Publication No. 2022 / 235904. The obtained tableting profile is shown in Figure 16. The data show that the material properties of ASD 3 are more similar to MCC PH 102 than to lactose.

[0088] Compression moldability provides additional information to describe the overall tableting behavior, taking into account other parameters that affect the process, such as porosity (described herein as solid content). The ability of a powder bed to aggregate or form a molded body provides an indicator of the powder's compression moldability. This behavior can be described, for example, by plotting the tablet tensile strength as a function of tablet solid content. The solid content was calculated according to common practice (i.e., the ratio of tablet density to true powder density).

[0089] Pure ASD 3 molded bodies prepared at approximately 55 MPa and 170 MPa have radial tensile strengths of 2.20 and 5.39, respectively. These values ​​are similar to those for MCC Ph 102 (RTS of 2.52 at 50 MPa and 6.80 at 200 MPa). See Figure 17.

[0090] In conclusion, the data demonstrate that the similarity of the material properties of ASD 3 to the MCC similarity of AMG 510:HPMCAS-M SDD to MCC allows for MCC reduction, which is advantageous for increasing the drug load in the tablet. Subsequently, pharmaceutical compositions were prepared using ASD 3 as shown in Example 4 below.

[0091] Example 4 - Pharmaceutical composition of ASD 3 This example describes the preparation of three pharmaceutical compositions using ASD 3. Specifically, three formulations containing 4% ASD 3, 71% ASD, and 94% ASD were prepared. Subsequently, the blend containing 71% ASD was formed into tablets.

[0092] [Table 7]

[0093] A 5 g blend was prepared using the components shown in Table 7. First, MCC and croscarmellose were weighed and transferred to a 20 ml plastic scintillation vial. Next, ASD 3 was weighed and added to the same scintillation vial. Finally, lactose was weighed and added. The vial was mounted on an acoustic mixer (LabRAM, Resodyn Acoustic Mixers, MT, USA) and the components were mixed at 75% intensity for 2 minutes. Subsequently, the blend was manually mixed with a spatula to ensure that the contents did not adhere to the vial walls. An electrostatic discharge gun was also used. Next, magnesium stearate was weighed and added to the blend. The final blend was further mixed at 75% intensity for another 2 minutes. This prepared blend was used for the dissolution experiment described below. The results are shown in Figure 18.

[0094] [Table 8]

[0095] A blend for 10 tablets was prepared using the components shown in Table 8. All components were weighed and transferred to a 20 ml plastic scintillation vial, except for the magnesium stearate. The vial was mounted on an acoustic mixer (LabRAM, Resodyn Acoustic Mixers, MT, USA) and the components were mixed at 75% intensity for 2 minutes. Subsequently, the blend was manually mixed with a spatula to ensure that the contents did not adhere to the vial walls. An electrostatic discharge gun was also used. Next, the magnesium stearate was weighed and added to the blend. The final blend was mixed further for another 2 minutes at 75% intensity. This prepared blend was then tabletized as described below.

[0096] The tablets were prepared by compression on a Korsch XP1 with the following settings: insertion depth = 6.5–6.7 mm, filling depth = 12.0 mm, target tablet weight = 678.9 mg, tool - Natoli 13 mm flat plate TSM B, upper punch - 0.5118”, lower punch - 0.5118”, and die - 0.5118”. These tablets were used for dissolution experiments as described below. The results are shown in Figure 19.

[0097] [Table 9]

[0098] A 2.2 g blend was prepared using the components shown in Table 9. All components were weighed and transferred to a 20 ml plastic scintillation vial. The vial was mounted on an acoustic mixer (LabRAM, Resodyn Acoustic Mixers, MT, USA) and the components were mixed at 75% intensity for 2 minutes. Subsequently, the blend was manually mixed with a spatula to ensure that the contents did not adhere to the vial walls. An electrostatic discharge gun was also used. The final blend was further mixed for another 2 minutes at 75% intensity. This prepared blend was used for the dissolution experiment described below. The results are shown in Figure 20.

[0099] Dissolution: The dissolution properties of tablets containing 71% ASD were evaluated as described herein. Three tablets with a target weight of 678.925 mg were added to a separate 900 mL container (USP Apparatus II) of 50 mM phosphate buffer pH 6.8 containing 0.2% SDS w / w, and samples were collected at time points 0, 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes (RPM increased to 250 from 90 to 120 minutes). Each sample was subjected to HPLC using a C18 column as the stationary phase under the conditions shown in Table 10. The mobile phase was water with 0.1% trifluoroacetic acid and acetonitrile. This method used a wavelength of 245 nm for detection and quantification, with 32% acetonitrile and 68% acetonitrile over 6 minutes.

[0100] [Table 10]

[0101] The solubility properties of the blend containing 4% ASD were evaluated as described above. 500.00 mg (4% SDD) of the target weight was added to three separate 150 mL containers of 50 mM phosphate buffer pH 6.8 containing 0.2% SDS w / w, and samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes (RPM increased to 250 between 90 and 120 minutes). Each sample was subjected to HPLC using a C18 column as the stationary phase under the conditions shown in Table 10. The mobile phase was water and acetonitrile containing 0.1% trifluoroacetic acid. This method used a wavelength of 245 nm for detection and quantification, with 32% acetonitrile and 68% acetonitrile over 6 minutes.

[0102] The solubility properties of the blend containing 94% ASD were evaluated as described herein. 319.1 mg of the target weight was added to three separate 900 mL containers of 50 mM phosphate buffer pH 6.8 containing 0.2% SDS w / w, and the samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes (RPM increased to 250 from 90 to 120 minutes). Each sample was subjected to HPLC using a C18 column as the stationary phase under the conditions shown in Table 10. The mobile phase was water with 0.1% trifluoroacetic acid and acetonitrile. This method used a wavelength of 245 nm for detection and quantification, with 32% acetonitrile and 68% acetonitrile over 6 minutes.

Claims

1. An amorphous solid dispersion (ASD) comprising sotracib and at least one polymer selected from the group consisting of cationic acrylate copolymers, vinylpyrrolidone acetate copolymers, cellulose polymers, and combinations thereof.

2. The ASD according to claim 1, wherein the sotrasib is essentially free of crystalline sotrasib.

3. The ASD according to claim 1 or 2, wherein there is no crystalline sotrabe detectable by XRPD.

4. The ASD according to any one of claims 1 to 3, wherein the at least one polymer comprises a cationic acrylate copolymer.

5. The ASD according to claim 4, wherein the cationic acrylate copolymer comprises a polymethacrylate polymer.

6. The ASD according to any one of claims 1 to 5, wherein the cationic acrylate copolymer comprises a copolymer based on monomers including aminoalkyl methacrylate and alkyl methacrylate.

7. The ASD according to any one of claims 1 to 6, wherein the cationic acrylate copolymer comprises a copolymer based on monomers including 2-dimethylaminoethyl methacrylate and alkyl methacrylate.

8. The ASD according to any one of claims 1 to 7, wherein the cationic acrylate copolymer comprises a copolymer based on monomers including 2-dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

9. The ASD according to claim 8, wherein the cationic acrylate copolymer is based on a monomer comprising 2-dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a monomer ratio of 2:1:

1.

10. The ASD according to any one of claims 1 to 9, wherein the cationic acrylate copolymer is poly((2-dimethylaminoethyl) methacrylate, butyl methacrylate, methyl methacrylate) (2:1:1).

11. The ASD according to any one of claims 1 to 10, wherein the vinylpyrrolidone-acetate copolymer comprises a copolymer based on a monomer including an N-vinyllactam monomer and a vinyl acetate monomer.

12. The ASD according to claim 11, wherein the N-vinyllactam monomer comprises N-vinylpyrrolidone.

13. The ASD according to claim 11 or 12, wherein the acetate monomer comprises vinyl acetate.

14. The ASD according to any one of claims 11 to 13, wherein the polymer comprises one or more polymers selected from povidone, copovidone, polyvinyl acetate and combinations thereof.

15. The ASD according to any one of claims 11 to 14, wherein the ratio of N-vinyl lactam monomer to acetate monomer is 6:

4.

16. The ASD according to any one of claims 1 to 22, wherein the at least one polymer comprises a random copolymer.

17. The ASD according to any one of claims 1 to 23, wherein the at least one polymer comprises one or more cellulose polymers selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylcellulose, and combinations thereof.

18. The ASD according to claim 24, wherein the cellulose polymer comprises hydroxypropyl methylcellulose acetate succinate.

19. An ASD according to any one of claims 1 to 16, having a D50 of 3 μm to 10 μm.

20. The ASD according to claim 19, wherein D50 is 3 μm to 7 μm.

21. The ASD according to claim 20, wherein D50 is 4 μm to 6 μm.

22. An ASD according to any one of claims 19 to 21, having a D10 of 1 μm to 2 μm.

23. An ASD according to any one of claims 19 to 22, having a D90 of 10 μm to 20 μm.

24. The ASD according to claim 17 or 18, having a D50 of 10 μm to 30 μm.

25. The ASD according to claim 24, having a D50 of 15 μm to 20 μm.

26. The ASD according to claim 24 or 25, having a D10 of 3 μm to 7 μm.

27. The ASD according to claim 26, having a D90 of 30 μm to 50 μm.

28. An ASD according to any one of claims 1 to 27, having a weight ratio of sotrasib to the polymer of 1:50 to 10:

1.

29. The ASD according to claim 28, wherein the weight ratio of sotrasib to the polymer is 1:10 to 1:

1.

30. The ASD according to claim 29, wherein the weight ratio of sotrasib to the polymer is 1:

3.

31. Sotrasib is 10 to 80% by weight of the ASD according to any one of claims 1 to 30.

32. The ASD according to claim 31, wherein sotrasib is 25% by weight of the ASD.

33. A process for producing amorphous drug dispersions (ASDs), (a) Mixing sotrasib with one or more polymers and a solvent to form a solution, (b) spray-dry the solution from step (a) to obtain the ASD A process that includes this.

34. The process according to claim 33, wherein the solvent comprises acetone, dichloromethane, or a mixture thereof.

35. The process according to claim 33 or 34, wherein the one or more polymers are selected from the group consisting of cationic acrylate copolymers, vinylpyrrolidone acetate copolymers, cellulose polymers, and combinations thereof.

36. The process according to any one of claims 33 to 35, wherein the sotrasib and the polymer are present in a weight ratio of 1:50 to 10:

1.

37. The process according to claim 36, wherein the weight ratio of sotrasib to polymer is 1:10 to 1:

1.

38. The process according to claim 37, wherein the weight ratio of sotrasib to the polymer is 1:

3.

39. The process according to any one of claims 33 to 38, wherein the ASD comprises sotrasib in an amount of 10 to 80% by weight of the ASD.

40. The process according to claim 39, wherein the ASD comprises sotrasib in an amount of 15 to 50% by weight of the ASD.

41. The process according to claim 40, wherein the ASD comprises sotrasib in an amount of 25% by weight of ASD.

42. ASD prepared by the process described in any one of claims 33 to 41.

43. The ASD according to claim 42, which is essentially free of crystalline sotrab.

44. The ASD according to claim 42, which is free from crystalline sotrabe in amounts detectable by XRPD.

45. A pharmaceutical composition comprising an ASD according to any one of claims 1 to 32 or 42 to 44, and a pharmaceutically acceptable excipient.

46. The pharmaceutical composition according to claim 45, comprising a disintegrant.

47. The pharmaceutical composition according to claim 46, wherein the disintegrant comprises cross-linked sodium carboxymethylcellulose (croscarmellose sodium), cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, pregelatinized starch, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, magnesium aluminum silicate, or a combination thereof.

48. The pharmaceutical composition according to claim 47, wherein the disintegrant comprises croscarmellose sodium, starch glycolate sodium, or a combination thereof.

49. The pharmaceutical composition according to claim 48, wherein the disintegrant is croscarmellose sodium.

50. A pharmaceutical composition according to any one of claims 46 to 49, comprising 2 to 10% (w / w) of the disintegrant.

51. A pharmaceutical composition according to any one of claims 46 to 49, comprising 6% (w / w) of the disintegrant and 94% (w / w) of the ASD.

52. The pharmaceutical composition according to claim 50, comprising 3% (w / w), 3.5% (w / w), or 6% (w / w) of the disintegrant.

53. A pharmaceutical composition according to any one of claims 45 to 50 or 52, comprising a diluent.

54. The pharmaceutical composition according to claim 53, wherein the diluent comprises lactose, dibasic calcium phosphate (DCP), mannitol, sorbitol, xylitol, calcium carbonate, magnesium carbonate, tribasic calcium phosphate, trehalose, microcrystalline cellulose, starch, or a combination thereof.

55. The pharmaceutical composition according to claim 54, wherein the diluent comprises lactose, dibasic calcium phosphate (DCP), mannitol, microcrystalline cellulose, starch, or a combination thereof.

56. The pharmaceutical composition according to claim 55, wherein the diluent comprises lactose, microcrystalline cellulose, or a combination thereof.

57. A pharmaceutical composition according to any one of claims 53 to 56, comprising 1 to 95% (w / w) of the diluent.

58. The pharmaceutical composition according to claim 57, comprising 92% (w / w) or 25% (w / w) of the diluent.

59. A pharmaceutical composition according to any one of claims 53 to 58, comprising 25% (w / w) lactose.

60. A pharmaceutical composition according to any one of claims 53 to 58, comprising 23% (w / w) lactose and 69% (w / w) microcrystalline cellulose.

61. A pharmaceutical composition according to any one of claims 45 to 50 or 52 to 60, comprising a lubricant.

62. The pharmaceutical composition according to claim 61, wherein the lubricant comprises magnesium stearate, calcium stearate, oleic acid, caprylic acid, stearic acid, magnesium isovalerate, calcium laurate, magnesium palmitate, behenic acid, glyceryl behenate, glyceryl stearate, sodium stearyl fumarate, potassium stearyl fumarate, zinc stearate, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, talc, polyethylene glycol, hydrogenated vegetable oil, or a combination thereof.

63. The pharmaceutical composition according to claim 61, wherein the lubricant is magnesium stearate.

64. A pharmaceutical composition according to any one of claims 61 to 63, comprising 0.5 to 5% (w / w) of the lubricant.

65. The pharmaceutical composition according to claim 64, comprising 0.6% (w / w) or 1% (w / w) of the lubricant.

66. The pharmaceutical composition according to claim 45, comprising 94% (w / w) ASD 3 and 6% (w / w) croscarmellose sodium.

67. The pharmaceutical composition according to claim 45, comprising 70.7% (w / w) ASD3, 25.2% (w / w) lactose, 3.5% (w / w) croscarmellose sodium, and 0.6% (w / w) magnesium stearate.

68. The pharmaceutical composition according to claim 45, comprising 4% (w / w) ASD3, 69% (w / w) microcrystalline cellulose, 23% (w / w) lactose, 3% (w / w) croscarmellose sodium, and 1% (w / w) magnesium stearate.

69. A method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of sotrasib provided as an ASD according to any one of claims 1 to 32 or 42 to 44 or as a pharmaceutical composition according to any one of claims 45 to 68.

70. The method according to claim 69, wherein one or more cells of the cancer express the KRAS G12C mutant protein.

71. The method according to claim 69 or 70, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, cancer of unknown primary origin, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, or melanoma.

72. The method according to claim 71, wherein the cancer is non-small cell lung cancer.

73. The method according to claim 71, wherein the cancer is colorectal cancer.

74. The method according to claim 71, wherein the cancer is pancreatic cancer.

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