Claims for Patent: 12,037,306

Summary for Patent: 12,037,306

Title:	Methods of treating neurofibromatosis type 1 with N-((R))-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
Abstract:	The present disclosure relates to: a) a crystalline composition of essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) pharmaceutical compositions comprising the crystalline composition of essentially pure Form IV of N—((R)-2,3-dihvdroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and, optionally, a pharmaceutically acceptable carrier; and c) methods of treating a tumor, a cancer, or a Rasopathy disorder by administering the crystalline composition of essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to a subject in need thereof.
Inventor(s):	Erwin Irdam
Assignee:	Warner Lambert Co LLC
Application Number:	US17/821,035
Patent Claims:	1. A method of treating neurofibromatosis type 1 in a patient in need thereof comprising administering a pharmaceutical composition comprising 1 mg to 4 mg N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Form IV characterized by an XRPD pattern having peaks at 4.6±0.2, 13.5±0.2 and 16.7±0.2 degrees two theta. 2. The method of claim 1 wherein the pharmaceutical composition comprises 1 mg N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. 3. The method of claim 1 wherein the pharmaceutical composition comprises 2 mg N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. 4. The method of claim 1 wherein the pharmaceutical composition comprises 3 mg N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. 5. The method of claim 1 wherein the pharmaceutical composition comprises 4 mg N'((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. 6. A method of treating neurofibromatosis type 1 in a patient in need thereof comprising administering a pharmaceutical composition comprising 1 mg to 4 mg N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Form IV characterized by an XRPD pattern substantially as shown in FIG. 1A. 7. The method of claim 1, wherein the pharmaceutical composition is a capsule comprising about 1 mg of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt % to about 1.5 wt/wt % of the crystalline composition of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c) about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and a gelatin capsule which encapsulates components a-d. 8. The method of claim 1, wherein the pharmaceutical composition is a capsule comprising about 2 mg of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt % to about 1.5 wt/wt % of the crystalline composition of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c) about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e) a gelatin capsule which encapsulates components a-d. 9. The method of claim 1, wherein the pharmaceutical composition is a tablet. 10. A method of treating neurofibromatosis type 1 in a patient in need thereof comprising orally administering one or more pharmaceutical compositions comprising a crystalline composition that is 0.5 mg to 2 mg of essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. 11. The method of claim 10, wherein the crystalline composition contains no more than 0.2% by weight of the dimeric impurity PF-0091189 12. The method of claim 11, wherein the crystalline composition contains about 0.005% to about 0.19% by weight of dimeric impurity PF-0091189. 13. The method of claim 11, wherein the crystalline composition contains no detectable amount of dimeric impurity PF-0091189. 14. The method of claim 10, wherein the pharmaceutical composition is a capsule comprising about 1 mg of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt % to about 1.5 wt/wt % of the crystalline composition of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c) about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and a gelatin capsule which encapsulates components a-d. 15. The method of claim 10, wherein the pharmaceutical composition is a capsule comprising about 2 mg of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt % to about 1.5 wt/wt % of the crystalline composition of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c) about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d) about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e) a gelatin capsule which encapsulates components a-d. 16. The method of claim 10, wherein the pharmaceutical composition is a tablet.