SUSTAINED-RELEASE DOSAGE FORMS OF RUXOLITINIB

• US 20140135350A1
• Filed: 11/14/2013
• Published: 05/15/2014
• Est. Priority Date: 11/15/2012
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Yeleswaram, Krishnaswamy, Erickson-Viitanen, Susan, Williams, William V., Ni, Yong, Parikh, Bhavnish
• Granted Patent: US 10,166,191 B2
• Time in Patent Office: Days
• US Class Current: 514/265.1
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/14 : Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention relates to sustained-release formulations and dosage forms of ruxolitinib, or a pharmaceutically acceptable salt thereof, which are useful in the treatment of Janus kinase-associated diseases such as myeloproliferative disorders.

Claims

1. A sustained-release dosage form comprising at least one active ingredient which is ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in said dosage form in an amount of about 10 to about 60 mg on a free base basis.

2. The sustained-release dosage form of claim 1 wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in said dosage form in an amount of about 25 mg on a free base basis.

3. The sustained-release dosage form of claim 1, wherein said active ingredient is ruxolitinib phosphate.

4. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human results in a mean peak plasma concentration (C_max) of ruxolitinib of about 700 nM or less.

5. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human results in a mean peak plasma concentration (C_max) of ruxolitinib of about 200 to about 700 nM.

6. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human results in a mean peak plasma concentration (C_max) of ruxolitinib of about 300 to about 400 nM.

7. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human state results in a mean time to peak plasma concentration (T_max) of ruxolitinib of about 1.5 hours or more.

8. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human results in a mean time to peak plasma concentration (T_max) of ruxolitinib of about 1.5 hours to about 5 hours.

9. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human results in a ratio of mean peak plasma concentration (C_max) to mean 12-hour plasma concentration (C_12h) of ruxolitinib of about 10 or less.

10. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human results in a ratio of mean peak plasma concentration (C_max) to mean 12-hour plasma concentration (C_12h) of ruxolitinib of about 4 or less.

11. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human results in a mean half-life (t_1/2) of from about 3.5 hours to about 11 hours.

12. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human results in a mean half-life (t_1/2) of from about 4 hours to about 8 hours.

13. The sustained-release dosage form of claim 1, wherein administration of a single dose of said dosage form to a human results in mean bioavailability (AUC_0-∞

) of ruxolitinib of about 3000 to about 4000 nM*h.

14. The sustained-release dosage form of claim 1, wherein administration of a single dose of said dosage form to a human results in mean bioavailability (AUC_0-∞

) of ruxolitinib of about 3100 to about 3800 nM*h.

15. The sustained-release dosage form of claim 1 comprising one or more cellulosic ethers.

16. The sustained-release dosage form of claim 15 comprising hydroxypropyl methylcellulose.

17. The sustained-release dosage form of claim 15 comprising from about 10% to about 30% by weight of hydroxypropyl methylcellulose.

18. The sustained-release dosage form of claim 1 which is in the form of a tablet or capsule.

19. The sustained-release dosage form of claim 1, comprising 25 mg of ruxolitinib on a free base basis, or a pharmaceutically acceptable salt thereof, wherein administration to a patient results in a mean ruxolitinib plasma level of about 75 to about 500 nM for at least about 8 hours.

20. The sustained-release dosage form of claim 19 comprising 12-13% ruxolitinib phosphate by weight on a free base basis and 19-13% by weight of one or more hypromelloses.

21. The sustained-release dosage form of claim 19 comprising 12.2% ruxolitinib phosphate by weight on a free base basis and 20% by weight or 22% by weight of one or more hypromelloses.

22. The sustained-release dosage form of claim 1, wherein administration to a patient results in a ruxolitinib plasma level of about 75 to about 500 nM for at least about 8 hours.

23. The sustained-release dosage form of claim 1, wherein administration to a patient results in a ruxolitinib plasma level of about 75 to about 500 nM for at least about 12 hours.

24. The sustained-release dosage form of claim 1 comprising 25 mg ruxolitinib phosphate on a free base basis, wherein administration of said dosage form to a patient for at least 16 weeks results in a mean decrease in mean base platelet count of no more than about 100×

10⁹/L.

25. The sustained-release dosage form of claim 24 wherein administration of said dosage form to a patient for at least 16 weeks results in a mean decrease in mean base platelet count of no more than about 80×

10⁹/L.

26. The sustained-release dosage form of claim 24 wherein administration of said dosage form to a patient for at least 16 weeks results in a mean decrease in mean base platelet count of no more than about 60×

10⁹/L.

27. The sustained-release dosage form of claim 24 wherein administration of said dosage form to a patient for at least 16 weeks results in a mean decrease in mean base platelet count of no more than about 40×

10⁹/L.

28. The sustained-release dosage form of claim 1, comprising 25 mg ruxolitinib phosphate on a free base basis, wherein administration of said dosage form to a patient for at least 16 weeks results in a mean decrease in mean hemoglobin of no more than about 15 g/L.

29. The sustained-release dosage form of claim 28 wherein administration of said dosage form to a patient for at least 16 weeks results in a mean decrease in mean hemoglobin of no more than about 10 g/L.

30. The sustained-release dosage form of claim 28 wherein administration of said dosage form to a patient for at least 16 weeks results in a mean decrease in mean hemoglobin of no more than about 8 g/L.

31. The sustained-release dosage form of claim 28 wherein administration of said dosage form to a patient for at least 16 weeks results in a mean decrease in mean hemoglobin of no more than about 6 g/L.

32. The sustained-release dosage form of claim 1 comprising (1) ruxolitinib phosphate, or a pharmaceutically acceptable salt thereof, (2) microcrystalline cellulose, (3) hypromellose, (4) lactose monohydrate, (5) colloidal silicon dioxide, (6) magnesium stearate, and (7) stearic acid.

33. A method of treating a disease associated with JAK activity in a patient in need thereof, comprising administering the dosage form of claim 1 to said patient, wherein said disease is selected from an autoimmune disease, a skin disorder, allograft rejection, graft versus host disease, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn'"'"'s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, autoimmune thyroid disorder, a viral disease, Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV), Human Papilloma Virus (HPV), cancer, a myeloproliferative disorder, an inflammatory disease, an inflammatory disease of the eye, iritis, uveitis, scleritis, conjunctivitis, an inflammatory disease of the respiratory tract, an inflammatory disease of the upper respiratory tract, an inflammatory disease of the lower respiratory tract, an inflammatory myopathy, myocarditis, ischemia reperfusion or a disorder related to an ischemic event, anorexia or cachexia resulting from or associated with cancer, fatigue resulting from or associated with cancer, a bone resorption disease, or mast cell activation syndrome.

34. The method of claim 33, wherein said autoimmune disease is bullous skin disorder.

35. The method of claim 34, wherein said bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP).

36. The method of claim 33, wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

37. The method of claim 36, wherein said skin disorder is psoriasis.

38. The method of claim 33, wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post PV-MF), post-essential thrombocythemia myelofibrosis (post ET-MF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), or systemic mast cell disease (SMCD).

39. The method of claim 38, wherein said disease is primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post PV-MF), post-essential thrombocythemia myelofibrosis (post ET-MF), polycythemia vera (PV), or essential thrombocythemia (ET).

40. The method of claim 38, wherein said disease is primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post PV-MF), or post-essential thrombocythemia myelofibrosis (post ET-MF).

41. The method of claim 33, wherein said cancer is a solid tumor, myeloma, prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi'"'"'s sarcoma, Castleman'"'"'s disease, pancreatic cancer, hematological cancer, lymphoma, leukemia, multiple myeloma, skin cancer, cutaneous T-cell lymphoma or cutaneous B-cell lymphoma.

42. The method of claim 33, wherein said bone resorption disease is osteoporosis, osteoarthritis, bone resorption associated with hormonal imbalance, bone resorption associated with hormonal therapy, bone resorption associated with autoimmune disease, or bone resorption associated with cancer.

43. The method of claim 33, wherein said oral dosage form is administered once daily.