Pharmaceutical formulations of Bruton's tyrosine kinase inhibitor

Abstract

PHARMACEUTICAL FORMULATIONS OF BRUTON'S TYROSINE KINASE INHIBITOR Abstract Described herein are pharmaceutical formulations of Bruton's tyrosine kinase (Btk) inhibitor I-((R)-3-(4-amino-3-(4-phenoxyphenyl)-IH-pyrazolo [3,4-d]pyrimidin- l-yl)piperidin-l-yl)prop-2-en-I-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. PHARMACEUTICAL FORMULATIONS OF BRUTON'S TYROSINE KINASE INHIBITOR Abstract FIG. 1 30 Formulation A 25 Formulation B Formulation C Formulation D 20 15 10 5 0 6 12 18 24 Nominal Time Post-Dose (h) Described herein are pharmaceutical formulations of Bruton's tyrosine kinase (Btk) inhibitor I-((R)-3-(4-amino-3-(4-phenoxyphenyl)-IH-pyrazole [3,4-d]pyrimidin- 1-yl)piperidin-l-yl)prop-2-en-I-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. 20 25 20 43 31 11 J un 2 02 5 P H A R M A C E U T I C A L F O R M U L A T I O N S O F B R U T O N ' S T Y R O S I N E 1 1 J u n 2 0 2 5 K I N A S E I N H I B I T O R A b s t r a c t F I G . 1 3 0 F o r m u l a t i o n A 2 0 2 5 2 0 4 3 3 1 2 5 F o r m u l a t i o n B Mean Ibrutinib Plasma Concentration (ng / mL) F o r m u l a t i o n C F o r m u l a t i o n D 2 0 1 5 1 0 5 0 6 1 2 1 8 2 4 N o m i n a l T i m e P o s t - D o s e ( h ) D e s c r i b e d h e r e i n a r e p h a r m a c e u t i c a l f o r m u l a t i o n s o f B r u t o n ' s t y r o s i n e k i n a s e ( B t k ) i n h i b i t o r I - ( R ) - 3 - ( 4 - a m i n o - 3 - ( 4 - p h e n o x y p h e n y l ) - I H - p y r a z o l o [ 3 , 4 - d ] p y r i m i d i n - 1 - y l ) p i p e r i d i n - l - y l ) p r o p - 2 - e n - I - o n e . A l s o d i s c l o s e d a r e m e t h o d s o f u s i n g t h e B t k i n h i b i t o r , a l o n e o r i n c o m b i n a t i o n w i t h o t h e r t h e r a p e u t i c a g e n t s , f o r t h e t r e a t m e n t o f a u t o i m m u n e d i s e a s e s o r c o n d i t i o n s , h e t e r o i m m u n e d i s e a s e s o r c o n d i t i o n s , c a n c e r , i n c l u d i n g l y m p h o m a , a n d i n f l a m m a t o r y d i s e a s e s o r c o n d i t i o n s . P H A R M A C E U T I C A L F O R M U L A T I O N S O F B R U T O N ' S T Y R O S I N E 1 1 J u n 2 0 2 5 K I N A S E I N H I B I T O R A b s t r a c t F I G . 1 3 0 F o r m u l a t i o n A 2 0 2 5 2 0 4 3 3 1 2 5 F o r m u l a t i o n B Mean Ibrutinib Plasma Concentration (ng / mL) F o r m u l a t i o n C F o r m u l a t i o n D 2 0 1 5 1 0 5 0 6 1 2 1 8 2 4 N o m i n a l T i m e P o s t - D o s e ( h ) D e s c r i b e d h e r e i n a r e p h a r m a c e u t i c a l f o r m u l a t i o n s o f B r u t o n ' s t y r o s i n e k i n a s e ( B t k ) i n h i b i t o r I - ( R ) - 3 - ( 4 - a m i n o - 3 - ( 4 - p h e n o x y p h e n y l ) - I H - p y r a z o l o [ 3 , 4 - d ] p y r i m i d i n - 1 - y l ) p i p e r i d i n - l - y l ) p r o p - 2 - e n - I - o n e . A l s o d i s c l o s e d a r e m e t h o d s o f u s i n g t h e B t k i n h i b i t o r , a l o n e o r i n c o m b i n a t i o n w i t h o t h e r t h e r a p e u t i c a g e n t s , f o r t h e t r e a t m e n t o f a u t o i m m u n e d i s e a s e s o r c o n d i t i o n s , h e t e r o i m m u n e d i s e a s e s o r c o n d i t i o n s , c a n c e r , i n c l u d i n g l y m p h o m a , a n d i n f l a m m a t o r y d i s e a s e s o r c o n d i t i o n s . P H A R M A C E U T I C A L F O R M U L A T I O N S O F B R U T O N ' S T Y R O S I N E 1 1 J u n 2 0 2 5 K I N A S E I N H I B I T O R A b s t r a c t 3 0 F o r m u l a t i o n A 2 0 2 5 2 0 4 3 3 1 2 5 Mean Ibrutinib Plasma Concentration (ng / mL) 2 0 1 5 1 0 5 0 6 1 2 1 8 2 4

Claims

1. An immediate release high-load solid tablet formulation comprising 60% w / w to 80% w / w ibrutinib and pharmaceutically acceptable excipients, wherein ibrutinib is a compound with the structure of Compound 1,ONH2NNNNOCompound 1; andthe 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     sodiumcarboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, 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; andsilica;wherein the solid tablet formulation is prepared using a process comprising a wet granulation method.2025204331   06 Aug 20262. An immediate release high-load solid tablet formulation comprising 60% w / w to 80% w / w ibrutinib and pharmaceutically acceptable excipients, wherein ibrutinib is a compound with the structure of Compound 1,Compound 1; andthe 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     sodiumcarboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum;one or more binders selected from the group consisting of hydroxypropyl cellulose and polyvinylpyrrolidone;a surfactant, wherein the surfactant is sodium lauryl sulfate;a glidant, wherein the glidant is silica; anda lubricant;wherein the solid tablet formulation is prepared using a process comprising a wet granulation method.

3. The high-load solid tablet formulation of claim 1 or claim 2, wherein the one or more diluents is selected from the group consisting of lactose, cellulose, and microcrystalline cellulose.2025204331   06 Aug 20264. The high-load solid tablet formulation of claim 3, wherein the one or more diluents is lactose; and lactose is present in an amount from about 8% w / w to about 14% w / w.

5. The high-load solid tablet formulation of any one of claims 1-4, wherein the one ormore disintegrating agents is croscarmellose.

6. The high-load solid tablet formulation of any one of claims 1-5, wherein theibrutinib is in an amount of about 140 mg, about 280 mg, about 420 mg, or about 560 mg in the tablet.Pharmacyclics LLCPatent Attorneys for the Applicant / Nominated Person SPRUSON & FERGUSON

Images