IP Library › Patent Application 15467414

Patent Application

App. No. 15/467,414

Pharmaceutical Formulations of a Bruton's Tyrosine Kinase Inhibitor

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Patent No.: US None
App. No.: 15/467,414

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Abstract

Described herein are pharmaceutical formulations of 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. Also disclosed are 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 (245)

1 . A method of treating cancer or graft versus host disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a high-load solid tablet formulation comprising ibrutinib and one or more pharmaceutically acceptable excipients,

wherein ibrutinib is a compound with the structure of Compound 1,

and wherein the high-load solid tablet formulation comprises at least 50% w/w of ibrutinib, and the excipients comprise,

one or more diluents selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, cellulose, microcrystalline cellulose, microcellulose, and talc;

one or more disintegrating agents 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;

one or more binders selected from the group consisting of hydroxypropyl cellulose and polyvinylpyrrolidone;

sodium lauryl sulfate;

colloidal silicon dioxide; and

magnesium stearate.

2 .- 6 . (canceled)

7 . The method of claim 1 , wherein the one or more disintegrating agents are 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, sodium starch glycolate, crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum.

8 . (canceled)

9 . The method of claim 1 , wherein the one or more diluents are lactose or microcrystalline cellulose, or a combination thereof.

10 .- 35 . (canceled)

36 . The method of claim 1 , wherein the excipients comprise lactose, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide and magnesium stearate.

37 . The method of claim 1 , wherein the excipients comprise intragranular and extragranular excipients; and the intragranular excipients comprise lactose, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose; and the extragranular excipients comprise croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

38 . The method of claim 1 , wherein excipients comprise:

intragranular excipients comprising:

lactose in an amount from about 5% w/w to about 20% w/w, about 8% w/w to about 15% w/w, or about 8% w/w to about 14% w/w;

microcrystalline cellulose in an amount from about 5% w/w to about 20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to about 15% w/w;

croscarmellose sodium in an amount from about 0 to about 10% w/w, about 2% w/w to about 5% w/w, or about 2% w/w to about 4% w/w; and

hydroxypropyl cellulose in an amount from about 0 to about 2% w/w, about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1% w/w; and

extragranular excipients comprising:

croscarmellose sodium in an amount from about 0 to about 5% w/w, about 2% w/w to about 5% w/w, or about 2% w/w to about 5% w/w;

sodium lauryl sulfate in an amount from about 0 to about 10% w/w, about 4% w/w to about 8% w/w, or about 5% w/w to about 6% w/w;

colloidal silicon dioxide in an amount from about 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w; and

magnesium stearate in an amount from about 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w.

39 . The method of claim 1 , wherein the excipients comprise intragranular and extragranular excipients; and the intragranular excipients comprise lactose, sodium lauryl sulfate, polyvinylpyrrolidone and croscarmellose sodium; and the extragranular excipients comprise croscarmellose sodium, sodium lauryl sulfate, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

40 . The method of claim 1 , wherein the excipients comprise

intragranular excipients comprising:

lactose in an amount from about 10% w/w to about 20% w/w, or about 12% w/w to about 15% w/w;

polyvinylpyrrolidone in an amount from about 0% w/w to about 5% w/w, or about 1% w/w to about 3% w/w;

croscarmellose sodium in an amount from about 1% w/w to about 10% w/w, or about 3% w/w to about 7% w/w; and

sodium lauryl sulfate in an amount from about 0% w/w to about 2% w/w, or about 0.5% w/w to about 1.5% w/w; and

extragranular excipients comprising:

croscarmellose sodium in an amount from about 0% w/w to about 5% w/w, or about 1% w/w to about 3% w/w;

sodium lauryl sulfate in an amount from about 0 w/w to about 10% w/w or about 0% w/w to about 4% w/w;

microcrystalline cellulose in an amount from about 1% w/w to about 10% w/w, or about 2% w/w to about 5% w/w;

colloidal silicon dioxide in an amount from about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w; and

magnesium stearate in an amount from about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w.

41 . The method of claim 1 , wherein the formulation comprises:

a) about 69% w/w to about 71% w/w of ibrutinib,

b) about 13% w/w to about 15% w/w of lactose monohydrate,

c) about 2% w/w to about 5% w/w of microcrystalline cellulose,

d) about 1% w/w to about 3% w/w of polyvinylpyrrolidone,

e) about 6% w/w to about 8% w/w of croscarmellose sodium,

f) about 1% w/w to about 4% w/w of sodium lauryl sulfate,

g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and

h) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

42 . The method of claim 1 , wherein the formulation comprises:

a) about 70% w/w of ibrutinib,

b) about 14% w/w of lactose monohydrate,

c) about 5% w/w of microcrystalline cellulose,

d) about 2% w/w of polyvinylpyrrolidone,

e) about 7% w/w of croscarmellose sodium,

f) about 1% w/w of sodium lauryl sulfate,

g) about 0.5% w/w of colloidal silicon dioxide, and

h) about 0.5% w/w of magnesium stearate.

43 . The method of claim 1 , wherein the formulation comprises:

a) about 70% w/w of ibrutinib,

b) about 14% w/w of lactose monohydrate,

c) about 2% w/w of microcrystalline cellulose,

d) about 2% w/w of polyvinylpyrrolidone,

e) about 7% w/w of croscarmellose sodium,

f) about 4% w/w of sodium lauryl sulfate,

g) about 0.5% w/w of colloidal silicon dioxide, and

h) about 0.5% w/w of magnesium stearate.

44 . The method of claim 1 , wherein the formulation comprises:

a) about 65% w/w to about 75% w/w of ibrutinib,

b) about 14% w/w to about 18% w/w of lactose monohydrate,

c) about 1% w/w to about 3% w/w of polyvinylpyrrolidone,

d) about 0.5% w/w to about 1.5% w/w of sodium lauryl sulfate,

e) about 5% w/w to about 15% w/w of crospovidone,

f) about 0.3% w/w to about 0.7% w/w of colloidal silicon dioxide, and

g) about 0.3% w/w to about 0.7% w/w of magnesium stearate.

45 . The method of claim 1 , wherein the formulation comprises:

a) about 59% w/w to about 61% w/w of ibrutinib,

b) about 13% w/w to about 15% w/w of lactose,

c) about 13% w/w to about 15% w/w of microcrystalline cellulose,

d) about 4% w/w to about 6% w/w of croscarmellose sodium,

e) about 5% w/w to about 7% w/w of sodium lauryl sulfate,

f) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and

g) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

46 . The method of claim 40 , wherein the formulation comprises:

a) about 59% w/w to about 61% w/w of ibrutinib,

b) about 13% w/w to about 14% w/w of lactose,

c) about 13% w/w to about 14% w/w of microcrystalline cellulose,

d) about 2% w/w to about 3% w/w of croscarmellose sodium (intragranular),

e) about 0.8% w/w to about 1.2% w/w of hydroxypropyl cellulose,

f) about 2% w/w to about 3% w/w of croscarmellose sodium (extragranular),

g) about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate,

h) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and

i) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

47 . The method of claim 40 , wherein the formulation comprises:

a) about 69% w/w to about 71% w/w of ibrutinib,

b) about 8% w/w to about 9% w/w of lactose,

c) about 8% w/w to about 9% w/w of microcrystalline cellulose,

d) about 2.5% w/w to about 3.5% w/w of croscarmellose sodium (intragranular),

e) about 2.5% w/w to about 3.5% w/w of croscarmellose sodium (extragranular),

f) about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate,

g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and

h) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

48 . The method of claim 1 , wherein ibrutinib is in an amount of about 140 mg, about 280 mg, about 420 mg, or about 560 mg in the tablet.

49 . The method of claim 1 , wherein the high-load solid tablet formulation is used for one tablet once a day dosing.

50 .- 54 . (canceled)

55 . The method of claim 1 , wherein ibrutinib is in an amount of about 70 mg to about 840 mg in the tablet.

56 . The method of claim 1 , wherein the formulation comprises about 60% w/w to about 80% w/w of ibrutinib.

57 . The method of claim 56 , wherein ibrutinib is in an amount of about 70 mg to about 840 mg in the tablet.

58 . The method of claim 56 , wherein ibrutinib is in an amount of about 140 mg, about 280 mg, about 420 mg, or about 560 mg in the tablet.

59 . The method of claim 36 , wherein the formulation comprises about 60% w/w to about 80% w/w of ibrutinib.

60 . The method of claim 59 , wherein ibrutinib is in an amount of about 70 mg to about 840 mg in the tablet.

61 . The method of claim 59 , wherein ibrutinib is in an amount of about 140 mg, about 280 mg, about 420 mg, or about 560 mg in the tablet.

62 . The method of claim 1 , wherein the formulation consists essentially of at least 50% w/w of ibrutinib,

one or more binders selected from the group consisting of hydroxypropyl cellulose and polyvinylpyrrolidone;

sodium lauryl sulfate;

colloidal silicon dioxide; and

magnesium stearate.

63 . The method of claim 1 , wherein the formulation consists essentially of:

a) about 69% w/w to about 71% w/w of ibrutinib,

b) about 13% w/w to about 15% w/w of lactose monohydrate,

c) about 2% w/w to about 5% w/w of microcrystalline cellulose,

d) about 1% w/w to about 3% w/w of polyvinylpyrrolidone,

e) about 6% w/w to about 8% w/w of croscarmellose sodium,

f) about 1% w/w to about 4% w/w of sodium lauryl sulfate,

g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and

h) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

64 . The method of claim 1 , wherein the formulation consists essentially of:

a) about 70% w/w of ibrutinib,

b) about 14% w/w of lactose monohydrate,

c) about 5% w/w of microcrystalline cellulose,

d) about 2% w/w of polyvinylpyrrolidone,

e) about 7% w/w of croscarmellose sodium,

f) about 1% w/w of sodium lauryl sulfate,

g) about 0.5% w/w of colloidal silicon dioxide, and

h) about 0.5% w/w of magnesium stearate.

65 . The method of claim 1 , wherein the formulation consists essentially of:

a) about 70% w/w of ibrutinib,

b) about 14% w/w of lactose monohydrate,

c) about 2% w/w of microcrystalline cellulose,

d) about 2% w/w of polyvinylpyrrolidone,

e) about 7% w/w of croscarmellose sodium,

f) about 4% w/w of sodium lauryl sulfate,

g) about 0.5% w/w of colloidal silicon dioxide, and

h) about 0.5% w/w of magnesium stearate.

66 . The method of claim 1 , wherein the formulation consists essentially of:

a) about 65% w/w to about 75% w/w of ibrutinib,

b) about 14% w/w to about 18% w/w of lactose monohydrate,

c) about 1% w/w to about 3% w/w of polyvinylpyrrolidone,

d) about 0.5% w/w to about 1.5% w/w of sodium lauryl sulfate,

e) about 5% w/w to about 15% w/w of crospovidone,

f) about 0.3% w/w to about 0.7% w/w of colloidal silicon dioxide, and

g) about 0.3% w/w to about 0.7% w/w of magnesium stearate.

67 . The method of claim 1 , wherein the formulation consists essentially of:

a) about 59% w/w to about 61% w/w of ibrutinib,

b) about 13% w/w to about 15% w/w of lactose,

c) about 13% w/w to about 15% w/w of microcrystalline cellulose,

d) about 4% w/w to about 6% w/w of croscarmellose sodium,

e) about 5% w/w to about 7% w/w of sodium lauryl sulfate,

f) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and

g) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

68 . The method of claim 40 , wherein the formulation consists essentially of:

a) about 59% w/w to about 61% w/w of ibrutinib,

b) about 13% w/w to about 14% w/w of lactose,

c) about 13% w/w to about 14% w/w of microcrystalline cellulose,

d) about 2% w/w to about 3% w/w of croscarmellose sodium (intragranular),

e) about 0.8% w/w to about 1.2% w/w of hydroxypropyl cellulose,

f) about 2% w/w to about 3% w/w of croscarmellose sodium (extragranular),

g) about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate,

h) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and

i) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

69 . The method of claim 40 , wherein the formulation consists essentially of:

a) about 69% w/w to about 71% w/w of ibrutinib,

b) about 8% w/w to about 9% w/w of lactose,

c) about 8% w/w to about 9% w/w of microcrystalline cellulose,

d) about 2.5% w/w to about 3.5% w/w of croscarmellose sodium (intragranular),

e) about 2.5% w/w to about 3.5% w/w of croscarmellose sodium (extragranular),

f) about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate,

g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and

h) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

70 . A method of treating cancer or graft versus host disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a solid tablet formulation comprising ibrutinib, one or more excipients;

wherein:

the excipients comprise:

one or more binders selected from the group consisting of hydroxypropyl cellulose and polyvinylpyrrolidone;

sodium lauryl sulfate;

colloidal silicon dioxide; and

magnesium stearate; and

wherein ibrutinib is a compound with the structure of Compound 1,

and is present at about 60% w/w to about 80% w/w and in an amount of about 70 mg to about 840 mg in the tablet.

71 . A method of treating cancer or graft versus host disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a solid tablet formulation comprising:

about 50% w/w to about 90% w/w of ibrutinib;

about 10% w/w to about 15% w/w lactose;

about 1% w/w to about 6% w/w microcrystalline cellulose;

about 1% w/w to about 5% w/w polyvinylpyrrolidone;

about 1% w/w to about 10% w/w croscarmellose sodium;

about 0.5% w/w to about 5% w/w sodium lauryl sulfate;

about 0.1% w/w to about 1.5% w/w colloidal silicon dioxide;

about 0.01% w/w to about 2% w/w magnesium stearate;

wherein ibrutinib is a compound with the structure of Compound 1,

and is in an amount of about 70 mg to about 840 mg in the tablet.

72 . The method of claim 71 , wherein the formulation comprises:

a) about 69% w/w to about 71% w/w of ibrutinib,

b) about 13% w/w to about 15% w/w of lactose monohydrate,

c) about 2% w/w to about 5% w/w of microcrystalline cellulose,

d) about 1% w/w to about 3% w/w of polyvinylpyrrolidone,

e) about 6% w/w to about 8% w/w of croscarmellose sodium,

f) about 1% w/w to about 4% w/w of sodium lauryl sulfate,

g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and

h) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

73 . The method of claim 71 , wherein the formulation consists essentially of:

a) about 69% w/w to about 71% w/w of ibrutinib,

b) about 13% w/w to about 15% w/w of lactose monohydrate,

c) about 2% w/w to about 5% w/w of microcrystalline cellulose,

d) about 1% w/w to about 3% w/w of polyvinylpyrrolidone,

e) about 6% w/w to about 8% w/w of croscarmellose sodium,

f) about 1% w/w to about 4% w/w of sodium lauryl sulfate,

g) about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and

h) about 0.4% w/w to about 0.6% w/w of magnesium stearate.

74 . A method of treating cancer or graft versus host disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a solid tablet formulation consisting essentially of:

about 50% w/w to about 90% w/w of ibrutinib;

about 10% w/w to about 15% w/w lactose;

about 1% w/w to about 6% w/w microcrystalline cellulose;

about 1% w/w to about 5% w/w polyvinylpyrrolidone;

about 1% w/w to about 10% w/w croscarmellose sodium;

about 0.5% w/w to about 5% w/w sodium lauryl sulfate;

about 0.1% w/w to about 1.5% w/w colloidal silicon dioxide;

about 0.01% w/w to about 2% w/w magnesium stearate;

wherein ibrutinib is a compound with the structure of Compound 1,

and is in an amount of about 70 mg to about 840 mg in the tablet.

75 . The method of claim 1 , wherein the method is a method of treating cancer.

76 . The method of claim 1 , wherein the cancer is a hematological malignancy.

77 . The method of claim 1 , wherein the cancer is a solid tumor.

78 . The method of claim 1 , wherein the cancer is a B-cell malignancy.

79 . The method of claim 1 , wherein the cancer is a leukemia, a lymphoma, or a myeloma.

80 . The method of claim 1 , wherein the cancer is selected from the group consisting of diffuse large B cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, marginal zone lymphoma, multiple myeloma, plasmacytoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, lymphomatoid granulomatosis, primary central nervous system lymphoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, and renal cell carcinoma.

81 . The method of claim 1 , wherein the cancer is chronic lymphocytic leukemia/small lymphocytic lymphoma.

82 . The method of claim 1 , wherein the cancer is Waldenström macroglobulinemia.

83 . The method of claim 1 , wherein the cancer is mantle cell lymphoma.

84 . The method of claim 1 , wherein the cancer is marginal zone lymphoma.

85 . The method of claim 1 , wherein the cancer is follicular lymphoma.

86 . The method of claim 1 , wherein the cancer is diffuse large B cell lymphoma.

87 . The method of claim 1 , wherein the method is a method of treating graft versus host disease.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 5, 2017

From: CHONG, CHING W.; KUEHL, ROBERT; TAN, HEOW; ATLURI, HARISHA

To: PHARMACYCLICS LLC

Reel/Frame 041858/0107 →