Modified release formulations of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile

Abstract

Modified release formulations, such as solid oral dosage forms comprising a core composition comprising Compound (I) and/or a pharmaceutically acceptable salt thereof; a sub-coating layer coating the core composition, said sub-coating layer comprising a polyvinyl alcohol and/or a hydroxypropyl methyl cellulose; and an enteric coating layer encapsulating the sub-coating layer and the core composition, said enteric coating layer comprising at least one polymer selected from an acrylic/methacrylic/ethacrylic acid homopolymer and copolymers thereof, a cellulose derivative, and a polyvinylpyrrolidone, and methods of administration of a Bruton's tyrosine kinase (BTK) inhibitor using said formulations.

What is claimed is: 
     
         1 . A modified release solid oral dosage form comprising:
 (a) a core composition comprising Compound (I) and/or a pharmaceutically acceptable salt thereof;   (b) a sub-coating layer coating the core composition, said sub-coating layer comprising a polyvinyl alcohol and/or a hydroxypropyl methyl cellulose; and   (c) an enteric coating layer encapsulating the sub-coating layer and the core composition, said enteric coating layer comprising at least one polymer selected from an acrylic/methacrylic/ethacrylic acid homopolymer and copolymers thereof, a cellulose derivative, and a polyvinylpyrrolidone.   
     
     
         2 . The modified release solid oral dosage form of  claim 1 , wherein the cellulose derivative is selected from cellulose acetate phthalate, cellulose acetate tritnellitate, methylcellulose, hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose succinate (HPMCS), and hydroxypropylmethylcellulose acetate succinate. (HPMCAS). 
     
     
         3 . The modified release solid oral dosage form of  claim 1  or  2 , wherein the sub-coating layer (b) comprises a polyvinyl alcohol, and the enteric coating layer (c) comprises a poly (methacrylic acid-co-ethyl acrylate) copolymer. 
     
     
         4 . The modified release solid oral dosage form of  claim 3 , wherein the polyvinyl alcohol is a pigmented polyvinyl alcohol. 
     
     
         5 . The modified release solid oral dosage form of any of  claims 1 - 4 , wherein the solid oral dosage form releases less than about 10% by weight of Compound (I) and/or a pharmaceutically acceptable salt thereof, in less than two hours at a pH less than or equal to about 2.0; at least about 80% by weight of Compound (I) and/or the pharmaceutically acceptable salt thereof in about 15 minutes to about two hours at a pH equal to or more than about 6.0; and any unreleased amount of Compound (I) is released by the end of about 7.5 hours at a pH equal to or more than about 6.0. 
     
     
         6 . The modified release solid oral dosage form of any of  claims 1 - 5 , wherein the core composition comprises Compound (I). 
     
     
         7 . The modified release solid oral dosage form of any of  claims 1 - 6 , wherein Compound (I) and/or a pharmaceutically acceptable salt thereof is an (E) and (Z) mixture of a mixture of (R) and (S) isomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 
     
     
         8 . The modified release solid oral dosage form of any of  claims 1 - 7 , wherein Compound (I) and/or a pharmaceutically acceptable salt thereof is an (E) and (Z) mixture of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 
     
     
         9 . The modified release solid oral dosage form of any of  claims 1 - 8 , wherein at least about 85% by weight of Compound (I) and/or said pharmaceutically acceptable salt thereof is the (E) isomer. 
     
     
         10 . The modified release solid oral dosage form of any of  claims 1 - 9 , wherein at least about 90% by weight of Compound (I) and/or said pharmaceutically acceptable salt thereof is the (E) isomer. 
     
     
         11 . The modified release solid oral dosage form of any of  claims 1 - 10 , wherein Compound (I) and/or a pharmaceutically acceptable salt thereof is a substantially pure amorphous form. 
     
     
         12 . The modified release solid oral dosage form of any of  claims 1 - 11 , wherein the core composition comprises about 30 mg to about 100 mg of Compound (I) and/or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The modified release solid oral dosage form of any of  claims 1 - 12 , wherein the core composition further comprises at least one excipient selected from fillers, drug release modifiers, disintegrants, and lubricants. 
     
     
         14 . The modified release solid oral dosage form of  claim 13 , wherein the filler comprises at least one of a cellulose derivative and a sugar molecule. 
     
     
         15 . The modified release solid oral dosage form of  claim 14 , wherein the cellulose derivative is microcrystalline cellulose. 
     
     
         16 . The modified release solid oral dosage form of  claim 15 , wherein the microcrystalline cellulose is Avicel® PH-101. 
     
     
         17 . The modified release solid oral dosage form of any of  claims 14 - 16 , wherein the sugar molecule is spray-dried mannitol. 
     
     
         18 . The modified release solid oral dosage form of  claim 17 , wherein the spray dried mannitol is Pearlitol® 100SD. 
     
     
         19 . The modified release solid oral dosage form of any of  claims 13 - 18 , wherein the drug release modifier is hydroxypropyl methyl cellulose. 
     
     
         20 . The modified release solid oral dosage form of  claim 19 , wherein the hydroxypropyl methyl cellulose is METHOCEL™ K 100 Premium CR. 
     
     
         21 . The modified release solid oral dosage form of any of  claims 13 - 20 , wherein the disintegrant is crosslinked homopolymer of N-vinyl-2-pyrrolidone (crospovidone). 
     
     
         22 . The modified release solid oral dosage form of  claim 21 , wherein the crospovidone is Kollidon™ CL. 
     
     
         23 . The modified release solid oral dosage form of any of  claims 13 - 22 , wherein the lubricant is sodium stearyl fumarate. 
     
     
         24 . The modified release solid oral dosage form of any of  claims 13 - 23 , comprising by weight of the core composition:
 about 6% to about 20% of Compound (I) and/or a pharmaceutically acceptable salt thereof;   about 34% to about 72% of microcrystalline cellulose;   about 5% to about 25% mannitol;   about 0% to about 20% of hydroxypropyl methyl cellulose;   about 0.5% to about 1.5% of crosslinked homopolymer of N-vinyl-2-pyrrolidone; and   about 0.5% to about 1.5% of sodium stearyl fumarate.   
     
     
         25 . The modified release solid oral dosage form of any of  claims 1 - 24 , wherein the core composition weighs about 83% to about 91% of the total weight of the solid oral dosage form. 
     
     
         26 . The modified release solid oral dosage form of any of  claims 1 - 25 , wherein the pigmented polyvinyl alcohol is OPADRY® II. 
     
     
         27 . The modified release solid oral dosage form of any of  claims 1 - 26 , wherein the sub-coating layer weighs about 2% to about 4% by weight of the solid oral dosage form. 
     
     
         28 . The modified release solid oral dosage form of any of  claims 1 - 27 , wherein the poly(methacrylic acid-co-ethyl acrylate) copolymer of the enteric coating layer is EUDRAGIT® L 30 D-55 or EUDRAGIT® L 100-55. 
     
     
         29 . The modified release solid oral dosage form of any of  claims 1 - 28 , wherein the enteric coating layer further comprises a solubilizer and a plasticizer/anti-tacking agent. 
     
     
         30 . The modified release solid oral dosage form of  claim 29 , wherein the solubilizer is a polyethoxylated sorbitan ester of oleic acid. 
     
     
         31 . The modified release solid oral dosage form of  claim 29  or  30 , wherein the solubilizer is Polysorbate 80 (Tween™ 80). 
     
     
         32 . The modified release solid oral dosage form of  claim 29 , wherein the plasticizer/anti-tacking agent is PlasACRYL™ T20. 
     
     
         33 . The modified release solid oral dosage form of any of  claims 1 - 32 , wherein the enteric coating layer weighs about 6% to about 20% of the total weight of the solid oral dosage form. 
     
     
         34 . The modified release solid oral dosage form of any of  claims 1 - 33 , wherein the enteric coating layer comprises by total weight of the solid oral dosage form:
 about 5% to about 16% of EUDRAGIT® L 30 D-55 or EUDRAGIT® L 100-55;   about 1% to about 3% of PlasACRYL™ T20; and   about 0.3% to about 0.8% of Polysorbate 80.   
     
     
         35 . The modified release solid oral dosage form of any of  claims 1 - 34 , wherein the core composition weighs about 80% to about 91% of the total weight of the solid oral dosage form. 
     
     
         36 . A method of inhibiting Bruton's tyrosine kinase (BTK) in a mammal in need thereof comprising administering to the mammal in need of such BTK inhibition a therapeutically effective amount of Compound (I) and/or a pharmaceutically acceptable salt thereof in a modified release solid oral dosage form of any of  claims 1 - 35 . 
     
     
         37 . A method of treating a disease mediated by Bruton's tyrosine kinase (BTK) in a mammal in need thereof comprising administering to the mammal in need of such disease treatment a therapeutically effective amount of Compound (I) and/or a pharmaceutically acceptable salt thereof in a modified release solid oral dosage form of any of  claims 1 - 35 . 
     
     
         38 . The method of  claim 37 , wherein the disease is an autoimmune disease, an inflammatory disease, or cancer. 
     
     
         39 . The method of  claim 37  or  38 , wherein the disease is acute necrotizing hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis, autoimmune inner ear disease (AIED), autoimmune retinopathy, axonal & neuronal neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP), demyelinating neuropathies, Devic's disease (neuromyelitis optica), experimental allergic encephalomyelitis, giant cell arteritis (temporal arteritis), Guillain-Barre syndrome, Lambert-Eaton syndrome, chronic Meniere's disease, myasthenia gravis, neuromyotonia, opsoclonus-myoclonus syndrome, optic neuritis, paraneoplastic cerebellar degeneration, peripheral neuropathy, perivenous encephalomyelitis, restless legs syndrome, stiff person syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis/Giant cell arteritis, transverse myelitis, multiple sclerosis, dysautonomia, age-related macular degeneration (wet and dry), corneal transplantation, encephalitis, meningitis, vasculitis, or systemic lupus erythematosus (SLE). 
     
     
         40 . The method of  claim 37  or  38 , wherein the disease is rheumatoid arthritis, psoriatic arthritis, lupus, uveitis, myasthenia gravis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, Sjogren's disease, Sjogren's dry eye, non-Sjogren's dry eye disease, psoriasis, pemphigus, urticaria, or asthma. 
     
     
         41 . The method of  claim 37  or  38 , wherein the disease is diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, small lymphocytic lymphoma (SLL), multiple myeloma, B-cell non-Hodgkin lymphoma, lymphoplamascytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. 
     
     
         42 . The method of any of  claims 37 - 41 , wherein the Compound (I) and/or the pharmaceutically acceptable salt thereof is administered in combination with one or more anti-cancer or anti-inflammatory agents.