Solid dispersions
Provided herein are solid dispersions and pharmaceutical compositions of Compound 1. Also provided are methods of treating a disease or disorder such as a cancer or infectious disease that comprises administering to a subject in need thereof the solid dispersions or compositions described herein.
1 . A solid dispersion comprising Compound 1 in an amorphous form and a matrix polymer, wherein Compound 1 has the following formula:
wherein the matrix polymer is selected from cellulose esters and cellulose ethers, polyalkylene oxides, polyacrylates and polymethacrylates, homopolymers and copolymers of N-vinyl lactams, polyacrylamides, vinyl acetate polymers, graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, polyvinyl acetate phthalate, oligo- and polysaccharides, and mixtures of two or more thereof.
2 . The solid dispersion of claim 1 , which is essentially free of Compound 1 in a crystalline form.
3 . The solid dispersion of claim 1 , which does not include Compound 1 in a crystalline form in an amount detectable by XRPD.
4 . The solid dispersion of claim 1 , wherein the matrix polymer comprises a polyacrylate or polymethacrylate.
5 . The solid dispersion of claim 1 , wherein the matrix polymer is poly((2-dimethylaminoethyl) methacrylate, butyl methacrylate, methyl methacrylate) (2:1:1).
6 . The solid dispersion of claim 1 , wherein the matrix polymer comprises one or more polymers selected from vinyl pyrrolidone polymers and vinyl caprolactam polymers.
7 . The solid dispersion of claim 1 , wherein the matrix polymer comprises one or more polymers selected from povidone, copovidone, and a graft copolymer of polyethylene glycol, polyvinyl acetate and polyvinylcaprolactam.
8 . The solid dispersion of claim 1 , wherein the matrix polymer comprises a graft copolymer of polyethylene glycol 6000, polyvinyl acetate and polyvinylcaprolactam, with a weight average molecular weight (Mw) of about 90,000 g/mol to about 140,000 g/mol.
9 . The solid dispersion of claim 1 , wherein the matrix polymer comprises a graft copolymer of polyethylene glycol 6000, polyvinyl acetate and polyvinylcaprolactam, with a weight ratio of about 13:30:57, wherein the graft copolymer has a weight average molecular weight (Mw) of about 118,000 g/mol.
10 . The solid dispersion of claim 1 , wherein the matrix polymer comprises one or more cellulose selected from hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate (HPMCP), and hydroxypropyl cellulose.
11 . The solid dispersion of claim 1 , wherein the weight ratio of Compound 1 to the matrix polymer ranges from about 1:50 to 10:1.
12 . The solid dispersion of claim 1 , wherein Compound 1 is present in the solid dispersion in an amount ranging from about 10-80% by weight.
13 . The solid dispersion of claim 1 , which is a solid dispersion comprising Compound 1 in an amorphous form dispersed in a copolymer, wherein the copolymer is poly((2-dimethylaminoethyl) methacrylate, butyl methacrylate, methyl methacrylate) (2:1:1), wherein the solid dispersion comprises about 30-50% by weight of Compound 1 and about 50-70% by weight of the copolymer.
14 . The solid dispersion of claim 1 , which is a solid dispersion comprising Compound 1 in an amorphous form dispersed in a graft copolymer of polyethylene glycol, polyvinyl acetate and polyvinylcaprolactam, wherein the solid dispersion comprises about 30-50% by weight of Compound 1 and about 50-70% by weight of the graft copolymer.
15 . The solid dispersion of claim 1 , which is a solid dispersion comprising Compound 1 in an amorphous form dispersed in hydroxypropylmethyl cellulose (HPMC), wherein the solid dispersion comprises about 30-50% by weight of Compound 1 and about 50-70% by weight of HPMC.
16 . The solid dispersion of claim 1 , which is a solid dispersion comprising Compound 1 in an amorphous form dispersed in hydroxypropyl cellulose, wherein the solid dispersion comprises about 30-50% by weight of Compound 1 and about 50-70% by weight of hydroxypropyl cellulose.
17 . A pharmaceutical composition comprising the solid dispersion of claim 1 .
18 . A method of preparing a pharmaceutical composition comprising mixing the solid dispersion according to claim 1 with a pharmaceutical excipient.
19 . A pharmaceutical composition comprising the solid dispersion of claim 13 and a pharmaceutically acceptable excipient.
20 . A pharmaceutical composition comprising the solid dispersion of claim 14 and a pharmaceutically acceptable excipient.
21 . A pharmaceutical composition comprising the solid dispersion of claim 15 and a pharmaceutically acceptable excipient.
22 . A pharmaceutical composition comprising the solid dispersion of claim 16 and a pharmaceutically acceptable excipient.
23 . A process for making a solid dispersion comprising:
(a) mixing Compound 1, a polymer, and a solvent to form a solution, wherein the polymer comprises an acrylate based polymer, an N-vinyl lactam polymer, or a cellulose; and
(b) spray-drying the solution of step (a), thereby obtaining the solid dispersion, wherein Compound 1 has the following formula:
24 . A method of treating cancer comprising a KRAS G12C mutation in a subject, the method comprising administering to the subject a therapeutically effective amount of the solid dispersion of claim 1 , wherein the cancer is pancreatic cancer, endometrial cancer, colorectal cancer, or lung cancer.
25 . The method of claim 24 , wherein the cancer is non-small cell lung cancer.