COMBINED COMPOSITION OF CEDAZURIDINE

Claims

1. A pharmaceutical dosage form comprising cedazuridine or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof, wherein at least a portion of the azacitidine is formulated for modified release.

2. The pharmaceutical dosage form according to claim 1, characterized in that cedazuridine is formulated for immediate release.

3. A pharmaceutical dosage form according to claim 1 or 2, characterized in that the portion of azacitidine that is formulated for modified release is formulated for intestinal release.

4. A pharmaceutical dosage form according to any one of the preceding claims, characterized in that the portion of azacitidine that is formulated for modified release is presented in the form of minitablets containing an enteric coating.

5. The pharmaceutical dosage form according to paragraph 4, characterized in that each minitablet of azacitidine contains: approximately 20-60% w / w azacitidine, wherein the percentage by weight is expressed relative to the total weight of the uncoated azacitidine minitablets; and one or more pharmaceutically acceptable excipients.

6. The pharmaceutical dosage form according to claim 5, characterized in that one or more pharmaceutically acceptable excipients are selected from the group consisting of lactose monohydrate, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), sodium croscarmellose, silicon dioxide and magnesium stearate.

7. A pharmaceutical dosage form according to any one of paragraphs 4-6, characterized in that the enteric coating contains polymethacrylate or its copolymers.

8. A pharmaceutical dosage form according to any one of paragraphs 4-7, characterized in that the enteric coating is sensitive to changes in pH in the intestine.

9. A pharmaceutical dosage form according to any one of paragraphs 4-8, characterized in that each minitablet of azacitidine additionally contains an insulating coating under the enteric coating.

10. The pharmaceutical dosage form according to paragraph 9, characterized in that the insulating coating contains hydroxypropyl methylcellulose (HPMC).

11. A pharmaceutical dosage form according to any of the preceding claims, characterized in that the azacitidine is formulated for modified release and is presented in the form of minitablets containing an enteric coating.

12. A pharmaceutical dosage form according to any one of the preceding claims, characterized in that substantially all of the azacitidine is formulated to be released outside the stomach.

13. A pharmaceutical dosage form according to any of the preceding claims, characterized in that the cedazuridine is not coated and is in the form of minitablets, tablets, powder, mixture, granules or pellets.

14. The pharmaceutical dosage form according to claim 13, characterized in that the minitablets, tablet, powder, mixture, granules or uncoated pellets contain approximately 10-40% w / w cedazuridine.

15. A pharmaceutical dosage form containing cedazuridine or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof, wherein: cedazuridine is formulated for immediate release; and Azacitidine is formulated as modified-release minitablets containing an enteric coating.

16. The pharmaceutical dosage form according to claim 15, characterized in that each azacitidine minitablet contains approximately 20-50% w / w azacitidine, wherein the percentage by weight is expressed relative to the total weight of the uncoated azacitidine minitablets.

17. A pharmaceutical dosage form according to claim 15 or 16, characterized in that each of the azacitidine minitablets contains an intragranular layer and an extragranular layer.

18. The pharmaceutical dosage form of claim 17, wherein the intragranular layer comprises about 20-50% by weight of azacitidine, about 10-60% by weight of lactose monohydrate, about 2-60% by weight of microcrystalline cellulose, about 1-10% by weight of sodium croscarmellose, about 0.5-10% by weight of hydroxypropyl methylcellulose (HPMC), about 0.1-3% by weight of silicon dioxide, and about 0.1-3% by weight of magnesium stearate, wherein the percentage by weight is expressed relative to the total weight of the uncoated azacitidine minitablets.

19. The pharmaceutical dosage form of claim 17 or 18, wherein the extragranular layer comprises about 1-60% w / w microcrystalline cellulose, about 1-10% w / w sodium croscarmellose, about 0.1-3% w / w silicon dioxide, and about 0.1-3% w / w magnesium stearate, wherein the percentage by weight is expressed relative to the total weight of the uncoated azacitidine minitablets.

20. A pharmaceutical dosage form according to any one of paragraphs 15-19, characterized in that the enteric coating contains polymethacrylate or its copolymers.

21. A pharmaceutical dosage form according to any one of paragraphs 15-20, characterized in that the enteric coating is sensitive to changes in pH in the intestine.

22. A pharmaceutical dosage form according to any one of paragraphs 15-21, characterized in that each azacitidine minitablet additionally contains an insulating coating.

23. The pharmaceutical dosage form according to paragraph 22, characterized in that the insulating coating contains hydroxypropyl methylcellulose (HPMC).

24. A pharmaceutical dosage form according to any one of claims 15-23, containing azacitidine and cedazuridine in a weight ratio of from about 1:1 to about 1:

3.

25. A pharmaceutical dosage form according to any one of claims 15-24, containing from about 60 mg to 100 mg of azacitidine.

26. A pharmaceutical dosage form according to any one of paragraphs 15-25, characterized in that cedazuridine is in the form of minitablets, tablets, powder, mixture, granules or uncoated pellets.

27. The pharmaceutical dosage form according to claim 26, characterized in that the cedazuridine minitablets, tablet, powder, mixture, granules or pellets contain about 10-90% w / w cedazuridine, wherein the percentage by weight is expressed relative to the total weight of the uncoated cedazuridine minitablets, tablet, powder, mixture, granules or pellets.

28. The pharmaceutical dosage form according to claim 26 or 27, characterized in that the minitablets, tablet, powder, mixture, granules or pellets of cedazuridine further contain about one or more components selected from the group consisting of lactose monohydrate, hydroxypropyl methylcellulose (HPMC), sodium croscarmellose, silicon dioxide and magnesium stearate.

29. A pharmaceutical dosage form according to any one of claims 15-28, containing from about 5 mg to 60 mg of cedazuridine.

30. A capsule containing a pharmaceutical dosage form according to any one of paragraphs 1 to 29.

31. A capsule containing: one or more azacitidine minitablets formulated for modified release, comprising azacitidine or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable excipients and an enteric coating; and immediate release cedazuridine in the form of an uncoated powder or mixtures containing cedazuridine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

32. A method of treating cancer in a patient, comprising administering a dosage form according to any one of claims 1-29 or a capsule according to claim 30 or 31 to a patient in need thereof.

33. The method according to claim 32, characterized in that the cancer is leukemia.

34. The method of claim 32, wherein the cancer is selected from the group consisting of previously treated or untreated, de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated, de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), malignant peripheral nerve sheath tumors (MPNST), neurological cancer, breast cancer, hormone receptor-positive tumor, head and neck cancer, primary central chondrosarcoma, myeloproliferative neoplasia (MPN), relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed Hodgkin's lymphoma, relapsed / refractory multiple myeloma (RRMM), metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer (mCRPC) and lung cancer.

35. The method according to any one of claims 32-34, characterized in that the cancer is selected from the group consisting of previously treated or untreated, de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated, de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML).

36. The method according to any one of paragraphs 32-35, characterized in that the cancer is associated with refractory anemia, refractory anemia with ringed sideroblasts, or refractory anemia with excess blasts.

37. The method according to any one of paragraphs 32-36, further comprising administering another therapeutic agent.

38. The method of claim 37, wherein the other therapeutic agent is one or more agents selected from the list consisting of: ADI-PEG 20, AMG-176, APG-115, APR-246, avelumab, bendamustine, bisantrene, brentuximab vedotin, capecitabine, CB-839, cisplatin, CS-01, cuzatuzumab, cyclophosphamide, cytarabine, dasatinib, daunorubicin, DCLL9718S, decitabine, deferasirox, dexamethasone, durvalumab, eltrombopag, enasidenib, entinostat, entrectinib, enzalutamide, epacadostat, erythropoietin, etoposide, evorpacept, filgrastim, fludarabine phosphate, flumatinib, gemcitabine, gemtuzumab ozogamicin, gilteritinib, GM-CSF, GSK2879552, HMPL-523, homogarringtonine, IBI188, ibrutinib, idarubicin, itacitinib, ivosidenib, jactinib, KRT-8602, LDE255, lenalidomide, lirilumab, LP-108, magrolimab, MAX-40279, mitoxantrone, liposomal mitoxantrone, mocetinostat, moxifloxacin, nivolumab, olutasidenib, omacetaxine, oxaliplatin, paclitaxel,pembrolizumab, pevonedistat, pinometostat, pracinostat, quizartinib, revlimid, rigosertib, rituximab, romidepsin, RP7214, S64315, S65487, sabatolimab, seculidemstat, selumetinib, siremadlin, sirolimus, SL-401, SNDX-5613, sorafenib, talazoparib, tamibarotene, tolinapant, trastuzumab, tucidinostat, tyrosine kinase inhibitor, uproleselan, Velcade, venetoclax, vincristine, visilizumab, vorinostat and vosaroxin., 39. A pharmaceutical dosage form according to any one of claims 1-29 or a capsule according to claim 30 or 31 for use in the treatment of cancer.

40. A pharmaceutical dosage form according to any one of claims 1 to 29 or a capsule according to claim 30 or 31 for use in the manufacture of a medicinal product for the treatment of cancer.

41. A pharmaceutical dosage form or capsule for use according to claim 39 or 40, characterized in that the cancer is leukemia.

42. A pharmaceutical dosage form or capsule for use according to claim 39 or 40, wherein the cancer is selected from previously treated or untreated, de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated, de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), malignant peripheral nerve sheath tumors (MPNST), neurological cancer, breast cancer, hormone receptor-positive tumor, head and neck cancer, primary central chondrosarcoma, myeloproliferative neoplasia (MPN), relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed Hodgkin's lymphoma, relapsed / refractory multiple myeloma (RRMM), metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer (mCRPC) and lung cancer.

43. A pharmaceutical dosage form or capsule for use according to paragraphs 39-42, characterized in that the cancer is selected from previously treated or untreated, de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated, de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), chronic myeloid leukemia (CML).

44. A pharmaceutical dosage form or capsule for use according to paragraphs 39-43, characterized in that the cancer is associated with refractory anemia, refractory anemia with ringed sideroblasts, or refractory anemia with excess blasts.

45. The use of a pharmaceutical dosage form according to any of paragraphs 1-29 or a capsule according to paragraph 30 or 31 for the treatment of cancer.

46. ​​The use of a pharmaceutical dosage form according to any one of claims 1-29 or a capsule according to claim 30 or 31 for the manufacture of a medicinal product for the treatment of cancer.

47. The use according to paragraph 45 or 46, characterized in that the cancer is leukemia.

48. The use according to claim 45 or 46, wherein the cancer is selected from previously treated or untreated, de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated, de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), malignant peripheral nerve sheath tumors (MPNST), neurological cancer, breast cancer, hormone receptor-positive tumor, head and neck cancer, primary central chondrosarcoma, myeloproliferative neoplasia (MPN), relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed Hodgkin's lymphoma, relapsed / refractory multiple myeloma (RRMM), metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer (mCRPC) and lung cancer.

49. The use according to any one of claims 45-48, characterized in that the cancer is selected from previously treated or untreated, de novo or secondary myelodysplastic syndrome (MDS) and previously treated or untreated, de novo or secondary chronic myelomonocytic leukemia (CMML).

50. The use according to any one of paragraphs 45-49, characterized in that the cancer is associated with refractory anemia, refractory anemia with ringed sideroblasts, or refractory anemia with excess blasts.