NZ731696B2

NZ731696B2 - Method for treating cancer

Info

Publication number: NZ731696B2
Application number: NZ731696A
Authority: NZ
Inventors: Heike Keilhack; Tsukasa Murase; Futoshi Shikata; Yuta Suzuki; Brett Truitt
Original assignee: Eisai R&D Management Co Ltd; Epizyme Inc
Filing date: 2015-11-17
Publication date: 2024-06-25

Abstract

The present invention relates to pharmaceutical compositions comprising inhibitor(s) of human histone methyltransferase EZH2, such as EPZ-6438, and methods of cancer therapy using the EZH2 inhibitor(s).

Claims

What is claimed is:

1. A solid pharmaceutical formulation comprising: N-((4,6-dimethyloxo-1,2- dihydropyridinyl)methyl)(ethyl(tetrahydro-2H-pyranyl)amino)methyl-4'- olinomethyl)-[1,1'-biphenyl]carboxamide: (“Compound 1”), wherein the formulation comprises: an amount of 40-60 wt.% of Compound 1, or a pharmaceutically acceptable salt of Compound 1 in an amount equivalent to 40-60 wt.% of Compound 1, or a combination of Compound 1 and a pharmaceutically acceptable salt of Compound 1 wherein the combination is present in an amount equivalent to 40-60 wt.% of nd 1; lactose monohydrate; low-substituted ypropyl cellulose in an amount of about 11-19 wt.%; sodium starch glycolate in an amount of about 3-7 wt.%; hydroxypropyl cellulose in an amount of about 1-10 wt.%; magnesium stearate in an amount of about 0.5-5 wt.%; and a g composition in an amount of about 1-10 wt.%.

2. The solid pharmaceutical formulation of claim 1, wherein the formulation comprises: a hydrobromide salt of Compound 1 in an amount equivalent to 50 wt.% ± 2.5 wt.% of Compound 1; e monohydrate in an amount of 16 wt.% ± 0.8 wt.%; a disintegrant comprising low-substituted hydroxypropyl cellulose in an amount of 15 wt.% ± 0.75 wt.%, and sodium starch ate; hydroxypropyl cellulose in an amount of 4 wt.% ± 0.2 wt.%; magnesium stearate in an amount of 2 wt.% ± 0.2 wt.%; and a coating ition in an amount of 3 wt.% ± 0.06 wt.%.

3. The solid pharmaceutical formulation of claim 2, wherein the egrant comprising low-substituted hydroxypropyl cellulose and sodium starch glycolate is in an amount of 20 wt.% ± 1.0 wt.%.

4. The solid pharmaceutical formulation of claim 1, wherein the formulation comprises: a hydrobromide salt of nd 1 in an amount of 55 wt.% ± 0.55 wt.%; e monohydrate in an amount of 16 wt.% ± 0.8 wt.%; a disintegrant comprising low-substituted hydroxypropyl cellulose in an amount of 15 wt.% ± 0.75 wt.%, and sodium starch glycolate; hydroxypropyl cellulose in an amount of 4 wt.% ± 0.2 wt.%; magnesium stearate in an amount of 2 wt.% ± 0.2 wt.%; and a coating composition in an amount of 3 wt.% ± 0.06 wt.%.

5. The solid pharmaceutical formulation of claim 4, wherein the disintegrant sing low-substituted hydroxypropyl cellulose and sodium starch glycolate is in an amount of 20 wt.% ± 1.0 wt.%.

6. The solid pharmaceutical formulation of claim 1, comprising lactose monohydrate in an amount of about 10-20 wt.%.

7. The solid pharmaceutical formulation of claim 1, comprising lactose monohydrate in an amount of 20 wt.% ± 5.0 wt.%.

8. The solid pharmaceutical formulation of any one of claims 1, 6, and 7, wherein Compound 1 is present as a hydrobromide salt of Compound 1 in an amount equivalent to about 40-60 wt.% of Compound 1.

9. The solid pharmaceutical formulation of claim 1, wherein the formulation comprises: a hydrobromide salt of Compound 1 in an amount of 50 wt.% ± 2.5 wt.%; lactose monohydrate; bstituted hydroxypropyl ose in an amount of 15 wt.% ± 0.75 wt.%; sodium starch glycolate in an amount of 5 wt.% ± 0.5 wt.%; hydroxypropyl cellulose in an amount of 4 wt.% ± 0.2 wt.%; magnesium stearate in an amount of 2 wt.% ± 0.2 wt.%; and a coating composition in an amount of 3 wt.% ± 0.06 wt.%.

10. The solid pharmaceutical composition of claim 9, comprising lactose monohydrate in an amount of about 20 wt.%.

11. The solid pharmaceutical formulation of claim 10, sing lactose monohydrate in an amount of 20 wt.% ± 5.0 wt.%.

12. The solid pharmaceutical formulation of claim 1, wherein the formulation ses: a hydrobromide salt of Compound 1 in an amount of 55 wt.% ± 0.55 wt.%; lactose monohydrate in an amount of 16 wt.% ± 0.8 wt.%; low-substituted hydroxypropyl cellulose in an amount of 15 wt.% ± 0.75 wt.%; sodium starch glycolate in an amount of 5 wt.% ± 0.5 wt.%; hydroxypropyl cellulose in an amount of 4 wt.% ± 0.2 wt.%; magnesium stearate in an amount of 2 wt.% ± 0.2 wt.%; and a coating ition in an amount of 3 wt.% ± 0.06 wt.%.

13. The solid pharmaceutical formulation of any one of claims 1-12, wherein the coating composition comprises hypromellose, talc, macrogol, titanium dioxide, and iron (III) oxide.

14. The solid pharmaceutical ation of claim 13, wherein the coating composition further comprises a colorant.

15. The solid ceutical formulation of claim 14, wherein the pharmaceutical formulation is in the form of a tablet.

16. The solid pharmaceutical formulation of claim 15, n the tablet consists of an al phase and an external phase.

17. The solid pharmaceutical formulation of claim 15 or 16, wherein the tablet comprises the equivalent of 100 mg, 200 mg, or 400 mg of Compound 1.

18. Use of the solid pharmaceutical composition according to any one of claims 1-17, in the manufacture of a medicament for treating cancer.

19. The use of claim 18, wherein the cancer comprises lymphoma, leukemia, or breast cancer.

20. The use of claim 19, wherein the lymphoma comprises a B cell lymphoma.

21. The use of claim 19, wherein the lymphoma ses a germinal cell lymphoma.

22. The use of claim 19, wherein the lymphoma ses follicular ma (FL), germinal center B-cell like diffuse large B-cell lymphoma (GCB DLBCL), Burkitt’s lymphoma, or Primary Mediastinal Large B-Cell Lymphoma (PMBCL).

23. The use of claim 19, wherein the cancer ses Colorectal adenocarcinoma, Cholangiocarcinoma, Pancreatic adenocarcinoma, Ewing’s sarcoma, Synovial sarcoma, Alveolar sarcoma, ar soft part sarcoma, Prostatic adenocarcinoma, Rhabdoid a, Malignant Rhabdoid tumor, or Urothelial carcinoma.

24. The use of any one of claims 18-23, wherein the cancer is refractory or resistant.

25. A process for making the solid pharmaceutical formulation of any one of claims 1-17, the process comprising: a) mixing a therapeutic agent, a t, a first disintegrant and/or a lubricant to form a first mixture, wherein the therapeutic agent is , a pharmaceutically acceptable salt thereof, or a combination thereof, and optionally one or more of the steps selected from: b) adding an aqueous, organic solvent-based solution, or an c/aqueous mixture solution comprising a binder to the first mixture to form a second mixture; c) granulating the second mixture to form wet granulates; d) drying the wet granulates to form dried granulates; e) size screening the dried granulates to obtain sized granulates; f) mixing the sized granulates with a lubricant, and a second egrant to form a third mixture; g) compressing the third mixture to form tablets; and h) applying a coating suspension to the tablets to generate film-coated tablets.

26. The process of claim 25, wherein in step a) the diluent is lactose drate and the first disintegrant is low-substituted hydroxypropyl cellulose.

27. The s of claim 25 or 26, wherein in step f) the lubricant is magnesium te and the second disintegrant is low-substituted hydroxypropyl cellulose.

28. The process of any one of claims 25-27, n the binder is hydroxypropyl cellulose. gaging 3E?“ Emma mEmmE wm?m wm?w 3221A! 05656 09900 HUGQAUHU Time (hr)