CRYSTALLINE FORMS OF A BRUTON'S TYROSINE KINASE INHIBITOR

• US 20180362535A1
• Filed: 08/23/2018
• Published: 12/20/2018
• Est. Priority Date: 06/04/2012
• Status: Active Grant

• Current Assignee: Pharmacyclics Incorporated (Abbvie Incorporated)
• Original Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Inventors: Purro, Norbert, Smyth, Mark S., Goldman, Erick, Wirth, David D.
• Granted Patent: US 10,294,231 B2
• Time in Patent Office: Days
• CPC Class Codes: A61J 1/035 Blister-type containers blisters in general B65D75/36
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4825 Proteins, e.g. gelatin gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• 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 15/02 : for disorders of the vagina
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• 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 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• 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 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: B65D 75/36 : one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages , the recess or recesses being preformed B65D73/0057, B65D73/0092 take precedence
• CPC Class Codes: C07B 2200/13 : Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

Described herein is the Bruton'"'"'s tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, including crystalline forms, solvates and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions that include the Btk inhibitor, as well as methods of using the Btk inhibitor, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

Claims

1-13. -13. (canceled)

14. A pharmaceutical formulation for oral administration comprising:

(a) about 40 mg to about 200 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

(b) about 40 wt % to about 50 wt % of diluent;

(c) about 3 wt % to about 10 wt % of disintegrating agent;

(d) about 2 wt % to about 7 wt % of surfactant; and

(e) lubricant.

15. The pharmaceutical formulation of claim 14, wherein the formulation is in the form of a capsule comprising about 140 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.

16. The pharmaceutical formulation of claim 14, wherein diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc.

17. The pharmaceutical formulation of claim 14, wherein diluent is selected from the group consisting of lactose, sucrose, dextrose, mannitol, xylitol, sorbitol, calcium phosphate, starches, modified starches, microcrystalline cellulose, and microcellulose.

18. The pharmaceutical formulation of claim 14, wherein diluent is selected from the group consisting of lactose, sucrose, mannitol, calcium phosphate, starches, modified starches, and microcrystalline cellulose.

19. The pharmaceutical formulation of claim 14, wherein diluent is microcrystalline cellulose.

20. The pharmaceutical formulation of claim 14, wherein disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch, cross-linked polymer, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum.

21. The pharmaceutical formulation of claim 14, wherein disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, sodium starch glycolate, crospovidone, sodium alginate, a clay, and a gum.

22. The pharmaceutical formulation of claim 14, wherein disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, croscarmellose, croscarmellose sodium, sodium starch glycolate, and crospovidone.

23. The pharmaceutical formulation of claim 14, wherein disintegrating agent is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and crospovidone.

24. The pharmaceutical formulation of claim 14, wherein disintegrating agent is croscarmellose sodium.

25. The pharmaceutical formulation of claim 14, wherein surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, and copolymers of ethylene oxide and propylene oxide.

26. The pharmaceutical formulation of claim 14, wherein surfactant is selected from the group consisting of sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, and copolymers of ethylene oxide and propylene oxide.

27. The pharmaceutical formulation of claim 14, wherein surfactant is selected from the group consisting of sodium lauryl sulfate, poloxamers, and copolymers of ethylene oxide and propylene oxide.

28. The pharmaceutical formulation of claim 14, wherein surfactant is sodium lauryl sulfate.

29. The pharmaceutical formulation of claim 14, wherein lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, sodium stearate, magnesium stearate, zinc stearate, and waxes.

30. The pharmaceutical formulation of claim 14, wherein lubricant is selected from the group consisting of stearic acid, talc, sodium stearyl fumarate, magnesium stearate, and zinc stearate.

31. The pharmaceutical formulation of claim 14, wherein lubricant is selected from the group consisting of stearic acid, talc, sodium stearyl fumarate, and magnesium stearate.

32. The pharmaceutical formulation of claim 14, wherein lubricant is magnesium stearate.

33. The pharmaceutical formulation of claim 14, wherein:

i. diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc;

ii. disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, sodium starch glycolate, crospovidone, sodium alginate, a clay, and a gum; and

iii. surfactant is selected from the group consisting of sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, and copolymers of ethylene oxide and propylene oxide.

34. The pharmaceutical formulation of claim 33, wherein the dosage form is a hard gelatin capsule.

35. The pharmaceutical formulation of claim 14, wherein:

i. diluent is selected from the group consisting of lactose, sucrose, dextrose, mannitol, xylitol, sorbitol, calcium phosphate, starches, modified starches, microcrystalline cellulose, and microcellulose;

ii. disintegrating agent is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and crospovidone; and

iii. surfactant is selected from the group consisting of sodium lauryl sulfate, poloxamers, and copolymers of ethylene oxide and propylene oxide.

36. The pharmaceutical formulation of claim 35, wherein the dosage form is a hard gelatin capsule.

37. The pharmaceutical formulation of claim 14, wherein:

i. diluent is selected from the group consisting of lactose, sucrose, mannitol, calcium phosphate, starches, modified starches, and microcrystalline cellulose;

ii. disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch, cross-linked polymer, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum; and

iii. surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, and copolymers of ethylene oxide and propylene oxide.

38. The pharmaceutical formulation of claim 37, wherein the dosage form is a hard gelatin capsule.

39. The pharmaceutical formulation of claim 14, wherein:

i. diluent is microcrystalline cellulose;

ii. disintegrating agent is croscarmellose sodium; and

iii. surfactant is sodium lauryl sulfate.

40. The pharmaceutical formulation of claim 14 comprising:

(a) about 40 wt % to about 50 wt % of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;

(b) microcrystalline cellulose;

(c) croscarmellose sodium; and

(d) sodium lauryl sulfate.

41. The pharmaceutical formulation of claim 40, wherein the dosage form is a hard gelatin capsule.