COMPOSITIONS AND METHODS FOR TREATING MYELOFIBROSIS

• US 20130243853A1
• Filed: 05/06/2013
• Published: 09/19/2013
• Est. Priority Date: 11/07/2010
• Status: Active Grant

• Current Assignee: Impact Biomedicines, Inc. (Bristol-Myers Squibb Company)
• Original Assignee: TargeGen, Inc. (Sanofi )
• Inventors: JAYAN, Arvind, CACACE, Janice, TEFFERI, Ayalew
• Granted Patent: US 10,391,094 B2
• Time in Patent Office: Days
• US Class Current: 424/452
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid

Abstract

Provided herein are compositions and methods for treating myelofibrosis in a subject. The methods comprise administering to the subject an effective amount of compound which is which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutical salt thereof or a hydrate thereof.

Claims

1. A capsule suitable for oral administration comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.

2. The capsule of claim 1, wherein the capsule contains about 10 mg to about 500 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.

3. The capsule of claim 2, wherein the capsule contains about 10 mg, about 40 mg, about 100 mg, or about 200 mg of the compound.

4. The capsule of claim 3, wherein the capsule contains about 100 mg of the compound.

5. The capsule of claim 1, wherein the weight ratio of the compound to microcrystalline cellulose in the admixture is between about 1:

1.5 to about 1;

15, wherein the weight for the compound in the weight ratio is the free base moiety weight of the compound.

6. The capsule of claim 1, wherein the weight ratio of the compound to sodium stearyl fumarate in the admixture is between about 5:

1 to about 50;

1, wherein the weight for the compound in the weight ratio is the free base moiety weight of the compound.

7. The capsule of claim 1, wherein microcrystalline cellulose is silicified microcrystalline cellulose.

8. The capsule of claim 1, wherein the compound is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

9. The capsule of claim 8, wherein the capsule contains an admixture of about 12 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate, about 122 mg of silicified microcrystalline cellulose, and about 1 mg of sodium stearyl fumarate.

10. The capsule of claim 8, wherein the capsule contains an admixture of about 47 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate, about 448 mg of silicified microcrystalline cellulose, and about 5 mg of sodium stearyl fumarate.

11. The capsule of claim 8, wherein the capsule contains an admixture of about 117 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

12. The capsule of claim 8, wherein the capsule contains an admixture of about 235 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate, about 357 mg of silicified microcrystalline cellulose, and about 6 mg of sodium stearyl fumarate.

13. The capsule of claim 1, wherein sodium stearyl fumarate is about 1% w/w of capsule fill weight.

14. The capsule of claim 7, wherein the weight ratio of the compound to silicified microcrystalline cellulose is about 1:

1.5.

15. The capsule of claim 7, wherein the weight ratio of the compound to silicified microcrystalline cellulose is about 1:

9.

16. The capsule of claim 1, wherein the capsule is a hard gelatin capsule.

17. A unit dosage form comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate.

18-25. -25. (canceled)

26. A method of treating myelofibrosis in a subject, comprising orally administering a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, and wherein the compound is in an admixture of (i) the compound, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate.

27. A method of treating myelofibrosis in a subject, comprising administering to the subject an effective amount of a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has previously received another myelofibrosis therapy with a JAK2 inhibitor which is not N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

28-53. -53. (canceled)

54. A method of preparing a capsule drug product comprising a) blending a lubricant with a compound that is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof to generate granules;

and b) mixing the granules of a) with an excipient.

55-60. -60. (canceled)

61. An article of manufacture comprising (a) an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, and (b) a package insert or a label indicating that the admixture is useful for treating myelofibrosis in a subject.

62-65. -65. (canceled)

66. An article of manufacture comprising (a) a compound which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutical salt thereof or a hydrate thereof, and (b) a package insert or a label indicating that the compound can be used for treating myelofibrosis in a subject, wherein the subject has previously received another myelofibrosis therapy with a JAK2 inhibitor which is not N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

67-69. -69. (canceled)