WO2023250343A1

WO2023250343A1 - Bcl2 formulations

Info

Publication number: WO2023250343A1
Application number: PCT/US2023/068767
Authority: WO
Inventors: David Michael HYMAN; Nora Chien Yee KU; Christopher M. Lindemann; James Michael PAUFF; Ruchit Sunil TRIVEDI
Original assignee: Loxo Oncology, Inc.
Priority date: 2022-06-21
Filing date: 2023-06-21
Publication date: 2023-12-28

Abstract

Disclosed are pharmaceutical formulations containing the compound of Formula (I): (I) and pharmaceutically acceptable salts thereof. Methods of treating disorders, including cancer, using the formulations are also disclosed.

Description

BCL2 Formulations

Field of the Invention

[0001] Disclosed herein are pharmaceutical formulations containing a BCL2 inhibitor.

Background

[0002] BCL2 inhibitors are used to treat hematological related disorders, including hematological cancers such as those of the blood and bone marrow (leukemias, lymphomas and myelomas, with or without transformation, where applicable) and other hematological disease, such as AL amyloidosis and post-transplant lymphoproliferative disorders.

[0003] Unfortunately, a cure for the aforementioned conditions still remains elusive and consequently, there exists a need for more and different therapies that may prove to be effective in their treatment.

The compound of Formula (I)

(CS -2-(( l//-Pyrrolo[2,3-/7]pyridine-5-yl)oxy)-A-((3-benzyl-5-nitro-3,4-dihydro-2//- benzo[/>][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’ -chi oro-5, 5-dimethyl-3, 4,5, 6-tetrahy dro-[l,L- biphenyl]-2-yl)methyl)piperazin-l-yl)benzamide (Loxo-338) and pharmaceutically acceptable salts thereof, exhibit BCL2 inhibitory activity. The compound of Formula (I) and pharmaceutically acceptable salts thereof, can be used to treat hematological disorders that can be treated with a BCL2 inhibitor. The compound of Formula (I) is insoluble in water, 0.1 mol/L HC1 solution and 0.1 mol/L NaOH solution.

[0004] A need exists for formulations containing the compound of Formula (I) and pharmaceutically acceptable salts thereof. Preferably, the formulations will increase the solubility of Loxo-338. This can lead to smaller pills/tablets/capsules, because less drug is needed to obtain the desired blood levels. This leads to maximizing ease of use for the patient, while also helping to increase patient compliance.

[0005] The compound and methods of making and using this compound including for the treatment of cell proliferative disorders are disclosed in WO18192462.

Summary

[0006] Disclosed herein are formulations containing the compound of Formula (I)

or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0007] Disclosed herein are methods of treating a patient that has a disorder that responds to the inhibition of BCL2, the method comprising administering a therapeutically effective amount of a formulation described herein.

[0008] Disclosed herein is a formulation for use in the treatment of a disorder that responds to the inhibition of BCL2.

[0009] Disclosed herein is a formulation comprising a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is obtainable by spray drying a solution comprising the compound of Formula (I), and at least one pharmaceutically acceptable excipient.

[00010] In an aspect, disclosed herein is a formulation comprising a compound of

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein the formulation is obtainable by spray drying a solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and combining the spray dried compound of Formula (T) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the solution comprises acetone and water.

[00011] In an aspect, disclosed herein is a process for preparing a formulation comprising a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein the formulation is prepared by spray drying a solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and combining the spray dried compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the solution comprises acetone and water.

Detailed Description

Tablet Size

[00012] The compound of Formula (I) or pharmaceutically acceptable salts thereof may be formulated as a capsule or tablet. In one embodiment, tablets are preferred.

[00013] The tablet and capsule formulations may contain about 5 to about 750 mg, about 10 to about 500 mg, about 50 to about 500 mg, about 25 to about 500 mg, about 10 to about 100 mg, about 25 to about 200 mg, about 100 to about 500 mg, about 10 to about 500 mg, about 100 to about 700 mg, about 250 to about 500 mg, about 300 to about 600 mg, about 50 to about 150 mg, or about 75 mg to about 150 mg, of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[00014] In an embodiment, the formulation contains about 5 mg to about 100 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the formulations may contain about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 25 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 45 mg, or about 5o mg, or about 55 mg, or about 60 mg, or about 65 mg, or about 70 mg, or about 75 mg, or about 80 mg, or about 95 mg, or about 100 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the formulation contains about 10 mg or about 25 mg or about 50 mg or about 75 mg or about 100 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[00015] In an embodiment, the formulation contains about 100 mg to about 500 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the formulations may contain about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 425 mg, or about 450 mg, or about 475 mg, or about 500 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[00016] In an embodiment, the formulation is a tablet contains about 10 mg, or about 25 mg, or about 100 mg of the compound of Formula (I).

Salts

[00017] Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2,- ethanedi sulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid p- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-carboxylic acid, glucoheptonic acid, 4.4’-methylenebis(3-hydroxy-2- ene-1 -carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

Excipients

[00018] Pharmaceutically acceptable excipients include diluents or fillers, binders, granulating agents, adhesives, polymers and copolymers, disintegrants, stabilizers, lubricants, anti-adherents, glidants, surfactants, dispersing or wetting agents, dissolution retardants or enhancers, adsorbents, buffers, chelating agents, preservatives, colors, flavors, sweeteners, or combinations thereof.

Diluents or Fillers

[00019] In some embodiments, the solid formulations provided herein comprise one or more diluents or fillers. As used herein, the terms " diluent” and “filler” are used interchangeably and are intended to mean an inert substance used as a filler to create the desired bulk, flow properties, and compression characteristics in the preparation of a solid dosage form. Such compounds include, but are not limited to dibasic calcium phosphate, kaolin, lactose, dextrose, magnesium carbonate, sucrose, mannitol, glucose or other monosaccharaides, dextrin or other polysaccharides, microcrystalline cellulose, powdered cellulose, cellulose derivatives, precipitated calcium carbonate, calcium sulfate, sorbitol, inositol, and starch and other materials known to one of ordinary skill in the art. In some embodiments, the diluent or filler is microcrystalline cellulose. In some embodiments the diluent or filler is mannitol. In some embodiments, the diluent or filler is a combination of microcrystalline cellulose and mannitol.

[00020] In some embodiments, the diluent or filler or combination thereof is present in the solid formulation in an amount from about 1 wt percent to about 99 wt percent, such as about 1 wt percent to about 90 wt percent, about 1 wt percent to about 80 wt percent, about 1 wt percent to about 70 wt percent, about 1 wt percent to about 60 wt percent, about 1 wt percent to about 50 wt percent, about 1 wt percent to about 40 wt percent, about 1 wt percent to about 30 wt percent, about 1 wt percent to about 20 wt percent, about 1 wt percent to about 10 wt percent, about 1 wt percent to about 5 wt percent, about 5 wt percent to about 99 wt percent, about 5 wt percent to about 90 wt percent, about 5 wt percent to about 80 wt percent, about 5 wt percent to about 70 wt percent, about 5 wt percent to about 60 wt percent, about 5 wt percent to about 50 wt percent, about 5 wt percent to about 40 wt percent, about 5 wt percent to about 30 wt percent, about 5 wt percent to about 20 wt percent, about 5 wt percent to about 10 wt percent, about 10 wt percent to about 99 wt percent, about 10 wt percent to about 90 wt percent, about 10 wt percent to about 80 wt percent, about 10 wt percent to about 70 wt percent, about 10 wt percent to about 60 wt percent, about 10 wt percent to about 50 wt percent, about 10 wt percent to about 40 wt percent, about 10 wt percent to about 30 wt percent, about 10 wt percent to about 20 wt percent, about 20 wt percent to about 99 wt percent, about 20 wt percent to about 90 wt percent, about 20 wt percent to about 80 wt percent, about 20 wt percent to about 70 wt percent, about 20 wt percent to about 60 wt percent, about 20 wt percent to about 50 wt percent, about 20 wt percent to about 40 wt percent, about 20 wt percent to about 30 wt percent, about 30 wt percent to about 99 wt percent, about 30 wt percent to about 90 wt percent, about 30 wt percent to about 80 wt percent, about 30 wt percent to about 70 wt percent, about 30 wt percent to about 60 wt percent, about 30 wt percent to about 50 wt percent, about 30 wt percent to about 40 wt percent, about 40 wt percent to about 99 wt percent, about 40 wt percent to about 90 wt percent, about 40 wt percent to about 80 wt percent, about 40 wt percent to about 70 wt percent, about 40 wt percent to about 60 wt percent, about 40 wt percent to about 50 wt percent, about 50 wt percent to about 99 wt percent, about 50 wt percent to about 90 wt percent, about 50 wt percent to about 80 wt percent, about 50 wt percent to about 70 wt percent, about 50 wt percent to about 60 wt percent, about 60 wt percent to about 99 wt percent, about 60 wt percent to about 90 wt percent, about 60 wt percent to about 80 wt percent, about 60 wt percent to about 70 wt percent, about 65 wt percent to about 99 wt percent, about 65 wt percent to about 90 wt percent, about 65 wt percent to about 85 wt percent, about 65 wt percent to about 80 wt percent, about 65 wt percent to about 75 wt percent, about 65 wt percent to about 70 wt percent, about 70 wt percent to about 99 wt percent, about 70 wt percent to about 90 wt percent, about 70 wt percent to about 80 wt percent, about 80 wt percent to about 99 wt percent, about 80 wt percent to about 90 wt percent, or about 90 wt percent to about 99 wt percent. In some embodiments, the diluent or filler or combination thereof is present in the solid formulation in an amount of about 1 wt percent, 5 wt percent, 10 wt percent, 20 wt percent, 30 wt percent, 40 wt percent, 50 wt percent, 60 wt percent, 69 wt percent, 70 wt percent, 79 wt percent, 80 wt percent, 90 wt percent, or about 99 wt percent. In some embodiments, the diluent or filler or combination thereof is present in the solid formulation in an amount of about 69 wt percent. In some embodiments, the diluent or filler or combination thereof is present in the solid formulation in an amount of about 72 wt percent. In some embodiments, the diluent or filler or combination thereof is present in the solid formulation in an amount of about 79 wt percent.

Binders

[00021] In some embodiments, the solid formulation includes a binder. Suitable examples of binders include, but are not limited to, povidone, copovidone, acacia, sodium alginate, starch, gelatin, saccharides (including glucose, sucrose, dextrose and lactose), molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methyl cellulose, veegum, larch arabolactan, polyethylene glycols, ethylcellulose, water, alcohols, waxes, polyvinylpyrrolidone (such as PVP K90), or mixtures thereof.

[00022] In some embodiments, the binder is magnesium stearate. In another embodiment, the binder is povidone. In an embodiment, the binder is copovidone, which is also known as polyvinylpyrrolidone-vinyl acetate copolymer. Granulating Agents

[00023] In some embodiments, the solid formulations provided herein comprise one or more granulating agent. Suitable examples of granulating agents include, but are not limited to solutions of povidone, copovidone, an aqueous preparation of cornstarch, molasses, methylcellulose, carboxymethylcellulose, glucose solution and microcrystalline cellulose, water, ethyl alcohol, isopropyl alcohol, acetone, or mixtures thereof.

Adhesives

[00024] In some embodiments, the solid formulations provided herein comprise one or more adhesives. Suitable examples of adhesives include, but are not limited to carbopol and polycarbophil, polyethylene oxide, polyvinyl alcohol, poly(N- acryloylpyrrolidine), reticulated gelatin, sodium alginate, natural gums, guar, xanthan, karaya, cellulose ethers, rifampicin, carbamazepine, griseofulvin, coenzyme Q10, lycopene, phytosterols, sodium diclofenac, etc.

Polymers and Copolymers

[00025] In some embodiments, the solid formulations provided herein comprise one or more polymers and copolymers. Suitable examples of polymers and copolymers include, but are not limited to macromolecular compounds of natural origin, e.g., sodium alginate, gelatin, chitosan and cellulose derivatives; semisynthetic polymers, e.g., cellulose derivatives; synthetic polymers, e.g., polyethylene glycols, pol oxamers, polylactides, polyamides, acrylic acid polymers, etc.; and fermentation products, e.g., xanthan gum. In some embodiments, the solid formulations provided herein comprise one or more polymers and copolymers. Suitable examples of polymers and copolymers include, but are not limited to macromolecular compounds of natural origin, e.g., sodium alginate, gelatin, chitosan and cellulose derivatives; semi synthetic polymers, e.g., cellulose derivatives; synthetic polymers, e.g., polyethylene glycols, pol oxamers, polylactides, polyamides, acrylic acid polymers, etc.; and fermentation products, e.g., xanthan gum.

Disintegrants

[00026] In some embodiments, the solid formulations comprise one or more disintegrants. As used herein, the term “disintegranf ’ is intended to mean a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, but are not limited to, starches such as corn starch, potato starch, tapioca starch, pre - gelatinized and modified starches thereof, sodium carboxymethyl starch (sodium starch glycolate) pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, sodium starch glycolate, calcium carbonate, sodium carbonate, sodium bicarbonate, cellulose and cellulose derivatives, such as calcium carboxymethyl cellulose, microcrystalline cellulose, carboxymethylcellulose calcium, croscarmellose sodium, croscarmellose calcium, carmellose calcium, cellulose polacrilin potassium, magnesium aluminum silicate (Veegum), sweeteners, clays, bentonite, alginic acid, sodium alginate, alginates, gums, agar, guar, locust bean, karaya, pectin, tragacanth, citrus pulp, crospovidone and other materials known to one of ordinary skill in the art . In some embodiments, the disintegrant is a cellulose derivative. In some embodiments, the cellulose derivative is croscarmellose sodium.

Stabilizers

[00027] In some embodiments, the solid formulations provided herein comprise one or more stabilizers. Suitable examples of stabilizers include, but are not limited to the following classes: sugar and sugar alcohol, e.g., Trehalose, Lactose, Sucrose, Mannitol, sorbitol; polymer, e.g., PEG 6000, PEG 3000, HPMC, PLGA, PVA, Pluronic-L92® PPO-PEO-PPO triblock copolymer, Dextran 35, Sodium alginate, PVP, Eudragit S100®; surfactant, e.g., Pluronic F68, Tyloxapol, Ammonium bicarbonate; protein, e.g., Casein sodium salt, Lactoferrin; salt, and amino acids, e.g., Leucine, Glycine.

Lubricants

[00028] In some embodiments, the solid formulations comprise one or more lubricants or lubricating agents. As used herein “lubricant” or “lubricating agent” means a substance used in solid dosage formulations to reduce friction during com pression. Exemplary lubricants include, but are not limited to, a stearate, such as zinc stearate, sodium stearate, calcium stearate, magnesium stearate, stearic acid, talc, mineral oil, a silica, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, and sodium lauryl sulfate. In some embodiments, the lubricant is a stearate. In some embodiments, the lubricant is magnesium stearate. In another embodiment, the lubricant is sodium stearyl fumarate (SSF).

[00029] In some embodiments, the solid formulation includes a lubricant in an amount of about 0.1 wt percent to about 5 wt percent; about 0.1 wt percent to about 3 wt percent; about 0.1 wt percent to about 1 wt percent; or about 0.1 wt percent to about 0.5 wt percent. In some embodiments, the solid formulation includes a lubricant in an amount of about 0.1 wt percent; about 0.2 wt percent; about 0.3 wt percent; about 0.4 wt percent; about 0.5 wt percent; about 0.6 wt percent; about 0.7 wt percent; about 0.8 wt percent; about 0.9 wt percent; or about 1 wt percent.

Anti -Adherents

[00030] In some embodiments, the solid formulations provided herein comprise one or more anti-adherents. Suitable examples of anti-adherents include, but are not limited to talc, cornstarch, metal stearates, sodium lauryl sulfate. Glidants

[00031] In some embodiments, the solid formulations comprise one or more glidants. As used herein, the term " glidant " is intended mean an agent used in solid dosage formulations to promote flowability of the solid mass. Such compounds include, but are not limited to, colloidal silica, colloidal silicon dioxide, fumed silica, cornstarch, talc, calcium silicate, magnesium silicate, tribasic calcium phosphate, silicon hydrogel and other materials known to one of ordinary skill in the art. In some embodiments, the glidant is silicon dioxide. In some embodiments, the glidant is fumed silica. In another embodiment, the glidant is colloidal silicon dioxide.

[00032] In some embodiments, the solid formulation includes a glidant in an amount of about 0. 1 wt percent to about 5 wt percent; about 0. 1 wt percent to about 3 wt percent; about 0.1 wt percent to about 1 wt percent; or about 0.1 wt percent to about 0.5 wt percent; or about 0.5 to about 1.5 wt percent; or about 0.3 to about 2 wt percent. In some embodiments, the solid formulation includes a glidant in an amount of about 0.1 wt percent; about 0.2 wt percent; about 0.3 wt percent; about 0.4 wt percent; about 0.5 wt percent; about 0.6 wt percent; about 0.7 wt percent; about 0.8 wt percent; about 0.9 wt percent; about 1 wt percent; about 1 .1 wt percent; about 1 .2 wt percent, about 1.3 wt percent, about 1.4 wt percent or about 1.5 wt percent.

Surfactants

[00033] In some embodiments, a surfactant is included in the solid formulation. Surfactants include both non- ionic and ionic cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include, for example, sodium lauryl sulfate (SLS), polyethoxylated fatty acids and their derivatives, such as polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4-150 mono dilaurate, and polyethylene glycol-20 glyceryl stearate; alcohol-oil transesterification products, for example, polyethylene glycol-6 corn oil; polyglycerized fatty acids for example polyglyceryl-6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol-20 sorbitan monooleate and sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example, polyethylene glycol-20 cetyl ether and polyethylene gly col-10- 100 nonyl phenol; sugar esters, for example, sucrose monopalmitate; poly oxy ethylene-polyoxypropylene block copolymers known as poloxamer; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate di sodium, and palmitoyl carnitine. In one embodiment, the surfactant is sodium lauryl sulfate (SLS).

Dispersing Agents

[00034] In some embodiments, the solid formulation includes one or more dispersing agents. Examples of dispersing agents include, but are not limited to , hydrophilic polymers , electrolytes, Tween® 60 or 80, polyvinylpyrrolidone (PVP ; commercially known as Plasdone® or copovidone), and the carbohydrate based dispersing agents such as, for example, hydroxypropyl celluloses (e.g., HPC, HPC - SL, and HPC - L), hydroxypropyl methylcelluloses(e.g., HPMC KI 00, HPMC K4M, HPMC K15M, and HPMC KI OOM), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxy propylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC AS), noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone / vinyl acetate copolymer (S630), 4- (1, 1,3,3 tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamines and poloxamers (also denoted polyoxypropylene - poly oxy ethyl ene block copolymers), including poloxamer 188, polox amer 237, poloxamer 338, poloxamer 407, or other block copolymers of ethylene oxide and propylene oxide, polyvi nylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S - 630), polyethylene glycol (PEG), e g., the polyethylene glycol has a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, polysorbate - 80, sodium alginate, gums, such as, e.g., gum traga canth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, polysorbate - 80, sodium alginate, polyethoxylated sorbitan monolaurate, povidone, copovidone, carbomers, alginates, chitosans and combinations thereof Plasticizers such as cellulose or triethyl cellulose can also be used as dispersing agents.

[00035] In some embodiments, the dispersing agent is hydroxypropyl methylcellulose acetate succinate (HPMC-AS). In some embodiments, the dispersing agent is a pol oxamer. In some embodiments, the dispersing agent is pol oxamer 188, which has an average molecular weight of about 8400 and a melting point of about 50-54 degrees centigrade In some embodiments, the dispersing agent is a combination of HPMC-AS and pol oxamer 188.

[00036] In some embodiments, the solid formulation includes one or more dispersing agents in an amount of about 0.1 wt percent to about 5 wt percent; about 0.1 wt percent to about 3 wt percent; about 0.1 wt percent to about 1 wt percent; or about 0.1 wt percent to about 0.5 wt percent. Tn some embodiments, the solid formulation includes one or more dispersing agents in an amount of about 0.1 wt percent; about 0.2 wt percent; about 0.3 wt percent; about 0.4 wt percent; about 0.5 wt percent; about 0.6 wt percent; about 0.7 wt percent; about 0.8 wt percent; about 0.9 wt percent; or about 1 wt percent.

Dissolution retardants or enhancers

[00037] In some embodiments, the solid formulations provided herein comprise one or more dissolution retardants or enhancers. Suitable examples of dissolution retardants or enhancers include, but are not limited to cyclodextrins, Croscarmellose Sodium, lackfruit starch, Sodium starch glycolate, crospovidone, Citric acid, Tartaric acid, Sodium Hydrogen Carbonate, Calcium Carbonate, di-Sodium Carbonate, Tocopherol polyethyleneglycol- 1000-succinate, Polyethylene glycol, polyvinyl acetate, polyvinylcaprolactame-based graft co-polymer, Hydroxypropyl methylcellulose acetate succinate, Chitosan, Sodium lauryl sulphate, Tween 20, Tween 40, Tween 60, Tween 80, sodium dodecyl sulphate, sodium lauryl ethoxy (3) sulphate, D-a- tocopherol polyethylene glycol 1000 succinate, D-a-tocopherol polyethylene glycol 1000 succinate, Capryol-90, Tween 80 and PEG-400, capryol 90, lauroglycol 90, carbitol, PEG 400, polypropylene glycol and cremophor EL, Sucrose laurate, Mannitol, MCC, Lactose.

Adsorbents

[00038] In some embodiments, the solid formulations provided herein comprise one or more adsorbent. Suitable examples of adsorbents include, but are not limited to silica, magnesium carbonate, kaolin, starch, bentonite, magnesium silicate, tricalcium phosphate, magnesium oxide, anhydrous calcium phosphate, and silicon dioxide, Sylysia 350, Fujicalin, Aerosil 200, Sylysia® 770, Neusilin.

Buffers

[00039] Tn some embodiments, the solid formulations provided herein comprise one or more buffers. Suitable examples of buffers include, but are not limited to Acetate, Citrate, Tartrate, Phosphate, Triethanolamine (TRIS).

Chelating agents

[00040] In some embodiments, the solid formulations provided herein comprise one or more chelating agents. Suitable examples of chelating agents include, but are not limited to Disodium EDTA, Dihydroxy ethyl glycine, Citric acid and Tartaric acid.

Preservatives

[00041] In some embodiments, the solid formulations provided herein comprise one or more preservatives. Suitable examples of preservatives include, but are not limited to antioxidants like vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium; amino acids, cysteine and methionine; Citric acid and sodium citrate; synthetic preservatives like the parabens, methyl paraben and propyl paraben.

Colors

[00042] In some embodiments, the solid formulations provided herein comprise one or more colors or pharmaceutically acceptable coatings. Suitable examples of colors include, but are not limited to the Color Additives Approved for Use in Drugs, Alumina, Annatto extract, Calcium carbonate, Canthaxanthin, Caramel, P-Carotene, Cochineal extract, Carmine, Potassium sodium copper chlorophyllin, Dihydroxyacetone, Bismuth oxychloride, Synthetic iron oxide, Ferric ammonium ferrocyanide, Ferric ferrocyanide, Chromium hydroxide green, Chromium oxide greens, Guanine, Mica-based pearlescent pigments, Pyrophyllite, Mica, Talc, Titanium dioxide, Aluminum powder, Bronze powder, Copper powder, Zinc oxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Blue No. 4, FD&C Green No 3, D&C Green No. 5, D&C Green No. 6, D&C Green No. 8, D&C Orange No. 4, D&C Orange No. 5, D&C Orange No. 10, D&C Orange No. 11, FD&C Red No. 3, FD&C Red No. 4, D&C Red No. 6, D&C Red No. 7, D&C Red No. 17, D&C Red No. 21 , D&C Red No. 22, D&C Red No. 27, D&C Red No. 28, D&C Red No. 30, D&C Red No. 31, D&C Red No. 33, D&C Red No. 34, D&C Red No. 36, D&C Red No. 39, FD&C Red No. 40, D&C Violet No. 2, FD&C Yellow No. 5, FD&C Yellow No. 6, D&C Yellow No. 7, D&C Yellow No. 8, D&C Yellow No. 10, D&C Yellow No. 11.

Flavors

[00043] In some embodiments, the solid formulations provided herein comprise one or more flavors. Suitable examples of flavors include, but are not limited to spices such as anise, cinnamon, cloves, ginger, nutmeg or flavor enhancers citric acid USP, lemon flavor, lime flavor, orange flavor, ethyl maltol, ethyl vanillin NF, fructose USP, fumaric acid NF, malic acid NF, maltol, menthol USP, monosodium glutamate NF, sodium chloride USP, stevia, tartaric acid NF and vanillin NF. Sweeteners

[00044] In some embodiments, the solid formulations provided herein comprise one or more sweeteners. Suitable examples of sweeteners include, but are not limited to acesulfame potassium, aspartame, confectioner’s sugar, dextrates, dextrose, fructose, mannitol, saccharin, sorbitol, sucralose, sucrose, xylitol etc.

[00045] The excipients described above may perform more than one function at a time, or they may perform different functions at the same time. For example, crospovidone may be a dispersing agent in a spray dried dispersion, and then it may act like a binding agent, when the tablet is formed.

[00046] As used herein, the terms “treating,” “to treat,” or “treatment” refers to restraining, slowing, stopping, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.

[00047] If desired, the formulations disclosed herein may be formulated as an extended release formulation

Tablets

[00048] In one aspect, the tablet comprises an inner portion, an intragranular portion and an extragranular portion. In one embodiment, the inner portion is prepared, it is then mixed with the intragranular portion to form a mixture that is called the “common blend,” and the common blend is then mixed with the extragranular portion. In this embodiment, after the common blend and the extragranular portions are mixed, the resulting mixture is 1) more or less homogenous (with more homogeneous mixtures being preferred), and 2) ready for further processing, e.g., being formed into a tablet. If a tablet is formed, it may be coated with an enteric coating, such as methacrylate copolymers, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetate succinates, cellulose acetate trimellitate. polyvinyl acetate phthalate, poly (methacrylic acid -ethyl acrylate 1:1), poly (methacrylic acid- methyl methacrylate! :1), poly (methacrylic acid- methyl methacrylate 1 :2), and cellulose acetate phthalate.

Inner Portion

[00049] The inner portion comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof. The inner portion typically further comprises one or more pharmaceutically acceptable excipients. In some embodiments the one or more pharmaceutically acceptable excipients comprises at least one binder. One preferred binder is copovidone. In an embodiment the one or more pharmaceutically acceptable excipients comprises at least one lubricant. A preferred lubricant is sodium lauryl sulfate. In one embodiment, the inner portion comprises at least one binder and at least one lubricant. For example, the inner portion comprises the compound of Formula (I) or a pharmaceutically acceptable salt thereof, copovidone and sodium lauryl sulfate. In a further example, the inner portion comprises the compound of Formula (I), copovidone and sodium lauryl sulfate.

[00050] Tn one embodiment, the inner portion, comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, the at least one binder and at least one lubricant is spray dried. When spray drying the compound of Formula (I) or a salt thereof, the compound or salt is combined with one or more pharmaceutically acceptable excipients and one or more pharmaceutically acceptable solvents. Useful solvents include any solvent that partially dissolves or completely dissolves the components to be spray dried. Examples of suitable solvents include acetone, di chloromethane, water, methanol, ethanol. In a preferred embodiment, the solvents are a mixture of acetone and water. In one embodiment, the ratio of the acetone to water is about 50:50 or about 60:40 or about 70:30 or about 80:20 or about 90:10. In a preferred embodiment, acetone:water (90: 10) is used. In a preferred embodiment, the mixture comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone and sodium lauryl sulfate is dissolved in a solvent and spray dried.

[00051] The resulting mixture (or solution, if all components completely dissolve) is then spray dried using techniques know in the art, such as spraying through a nozzle. The resulting droplets are dried and thereby result in solid particles that may be used in the formulations described herein.

[00052] In some embodiments, the inner portion comprises about 10 mg of the compound of Formula (I). In some other embodiments, the inner portion comprises about 25 mg of the compound of Formula (I). In other embodiments, the inner portion comprises about 100 mg of the compound of Formula (I).

[00053] The inner portion contains about 5 to about 25 wt %, or about 6 to about 20 wt %, or about 7 to about 18 wt %, or about 8 to about 15 wt %, or about 9 to 15 wt % or about 10 to 13 wt % of the compound of Formula (I). In one embodiment, the inner portion contains about 10 to about 13 wt % of the compound of Formula (I).

[00054] The inner portion further comprises about 10 to about 85 wt %, or about 20 to about 70 wt %, or about 25 to about 70 wt %, or about 20 to about 60 wt %, or about 30 to about 70 wt % or about 45 to about 70 wt % or about 45 to about 65 wt %, or about 50 to about 60 wt %, or about 55 to about 80 wt % of at least one binder. In one embodiment, the inner portion contains about 50 to about 60 wt % of at least one binder.

[00055] The inner portion further comprises about 0.5 to about 10 wt % or about 1 to about 8 wt %, or about 1 to about 7 wt %, or about 2 to about 6 wt %, or about 3 to about 5 wt % of at least one surfactant. In one embodiment, the inner portion contains about 4.5 wt % of at least one surfactant.

Intragranular Portion

[00056] The intragranular portion is mixed with the inner portion, to form a common blend. [00057] The intragranular portion comprises at least one diluent or filler. In an embodiment, a preferred diluent or filler is mannitol. It may also contain at least glidant. In an embodiment, a preferred glidant is silicon dioxide, such as colloidal silicon dioxide. It may also contain at least one lubricant. In an embodiment, a preferred lubricant is sodium stearyl fumarate. In a further embodiment, the intragranular portion comprises a diluent or filler, a glidant and a lubricant. In one preferred embodiment, the intragranular portion comprises mannitol, colloidal silicon dioxide and sodium stearyl fumarate.

[00058] The intragranular portion comprises about 5 to about 60 wt % or about 10 to about 45 wt% or about 12 to about 40 wt % or about 15 to about 35 wt %, or about 15 to about 25 wt %, or about 20 to about 30 wt %, or about 20 to about 25 wt % of at least one diluent or filler. In one preferred embodiment, the intragranular portion comprises about 24 wt % of at least one diluent or filler.

[00059] The intragranular portion comprises about 0.05 to about 7 wt % or about 0.05 to about 6 wt % or about 0.1 to about 5 wt % or, or about 0.1 to about 4 wt %, or about 0.1 to about 3 wt %, or about 0.5 to about 2 wt %, or about 0.7 to about 1.5 wt % of at least one glidant. Tn one preferred embodiment, the intragranular portion comprises about 1.0 wt % of at least one glidant.

[00060] The intragranular portion comprises about 0.05 to about 5 wt %, or about 0.1 to about 3 wt %, or about 0.2 to about 2 wt %, or less than 1 wt % of at least one lubricant. In one preferred embodiment, the intragranular portion comprises less than 1 wt % of at least one lubricant.

Extragranular Portion

[00061] The extragranular portion is combined with the common blend. The resulting mixture may be further processed or it may be compressed to form a tablet. The tablet may then be coated. Various sized and shaped tablets may be prepared. Various pharmaceutically acceptable coatings, some of which are described herein, may be applied to the tablet. [00062] The extragranular portion comprises at least one lubricant. Examples of suitable lubricants include sodium stearyl fumarate.

[00063] The extragranular portion comprises about 0.05 to about 5 wt %, or about 0.1 to about 3 wt %, or about 0.2 to about 2 wt %, or less than 1 wt % of at least one lubricant. In one preferred embodiment, the extragranular portion comprises less than 1 wt % of at least one lubricant.

[00064] In one aspect, the tablets described herein comprise the compound of Formula (I), at least one binder, at least one lubricant, at least one diluent or filler, at least one glidant, and at least one surfactant. The tablets comprise about 10 mg or about 25 mg, or about 50, or about 100 mg, or about 200 mg, or about 300 mg of the compound of Formula (I). In a more preferred embodiment, the tablet comprises about 10 mg or about 50, or about 100 mg of the compound of Formula (I). In one embodiment, the tablet comprises about 10 mg of the compound of Formula (I). In another embodiment, the tablet comprises about 50 mg of the compound of Formula (I). In an embodiment, the tablet comprises about 100 mg of the compound of Formula (I).

[00065] Tn an embodiment, the tablets described herein comprise about 8 to about 15 wt % of the compound of Formula (I).

[00066] In an embodiment, the tablets described herein comprise about 55 to about 61 wt % of at least one binder.

[00067] In an embodiment, the tablets described herein comprise about 2 to about 9 wt % of at least one surfactant.

[00068] In an embodiment, the tablets described herein comprise about 20 to about 27 wt % of at least one diluent or filler

[00069] In an embodiment, the tablets described herein comprise about 0.5 to about 3 wt % of at least one glidant.

[00070] In an embodiment, the tablets described herein comprise about 0.5 to about 3 wt % of at least one lubricant. [00071] In another embodiment, the tablets described herein comprise about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, about 55 to about 61 wt % of at least one binder, about 2 to about 9 wt % of at least one surfactant, about 20 to about 27 wt % of at least one diluent or filler, about 0.5 to about 3 wt % glidant, and about 0.5 to about 3 wt % of at least one lubricant, whereupon the total of all of the above percentages is less than or equal to 100 wt %.

[00072] In one aspect, the tablets described herein comprise the compound of Formula (I), copovidone, sodium lauryl sulfate, mannitol, colloidal silicon dioxide, and sodium stearyl fumarate. The tablets comprise about 10 mg or about 25 mg, or about 50, or about 100 mg, or about 200 mg, or about 300 mg of the compound of Formula (I). In a more preferred embodiment, the tablet comprises about 10 mg or about 50, or about 100 mg of the compound of Formula (I). In one embodiment, the tablet comprises about 10 mg of the compound of Formula (I). In another embodiment, the tablet comprises about 50 mg of the compound of Formula (I). In an embodiment, the tablet comprises about 100 mg of the compound of Formula (I).

[00073] Tn an embodiment, the tablets described herein comprise about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, [00074] In an embodiment, the tablets described herein comprise about 55 to about 61 wt % copovidone.

[00075] In an embodiment, the tablets described herein comprise about 2 to about 7 wt % sodium lauryl sulfate.

[00076] In an embodiment, the tablets described herein comprise about 20 to about 27 wt % mannitol.

[00077] In an embodiment, the tablets described herein comprise about 0.5 to about 3 wt % colloidal silicon dioxide.

[00078] In an embodiment, the tablets described herein comprise about 0.2 to about 2 wt % sodium stearyl fumarate. [00079] In an embodiment, the tablets described herein comprise about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, about 55 to about 61 wt % copovidone, about 2 to about 7 wt % sodium lauryl sulfate, about 20 to about 27 wt % mannitol, about 0.5 to about 3 wt % colloidal silicon dioxide, and about 0.2 to about 2 wt % sodium stearyl fumarate, whereupon the total of all of the above percentages is less than or equal to 100 wt %.

[00080] In an aspect, the compound of Formula (I) or pharmaceutically acceptable salt thereof is contained in a spray dried dispersion.

[00081] As used herein, the term “patient” refers to a human that was diagnosed with or needs treatment for a hematological related disorder that is treatable with the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[00082] As used herein, “prior therapy” refers to any therapy or course of treatment given to a cancer patient, to treat the cancer, before starting treatment with the compound of Formula (I) or a pharmaceutically acceptable salt thereof. Examples of prior therapy include, but are not limited to surgery and pharmaceuticals, e.g., chemotherapy. Any treatment of the cancer, where the cancer notwithstanding the stage, i.e., it is early stage, advanced or in between, is a prior therapy.

[00083] As used herein, the term “effective amount” refers to the amount or dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, upon single or multiple dose administration to the patient, provides an effective response in the patient under diagnosis or treatment.

[00084] An effective amount can be determined in view of the guidance provided herein, by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for a patient, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the daily (i.e., every 24 hours) dose regimen selected; the use of concomitant medication; and other relevant circumstances.

[00085] The daily dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is about 25 mg/day. In one aspect, the daily dose is about 50 mg/day. In one aspect, the daily dose is about 100 mg/day. In one aspect, the daily dose is about 150 mg/day. In one aspect, the daily dose is about 200 mg/day. In one aspect, the daily dose is about 250 mg/day. In one aspect, the daily dose is about 300 mg/day. In one aspect, the daily dose is about 350 mg/day. In one aspect, the daily dose is about 400 mg/day. The compound of Formula (I) may be in the form of the free base. However, it will be understood that the compound of Formula (I) is capable of forming salts. The compound of Formula (I) can react with any of a number of inorganic and organic bases to form pharmaceutically acceptable base addition salts. Such pharmaceutically acceptable base addition salts are described elsewhere, herein.

[00086] For the avoidance of doubt, when a dose is described herein, the dose refers to the amount of the free amine, i.e., non-salt version of the compound of Formula (I) that is administered. For example, a 200 mg dose would require more than 200 mg of a pharmaceutically acceptable salt of Formula (I), because the weight of the salt counterion must be included.

[00087] For example, as illustrated below, about 238 mg of the tosylate salt of Loxo- 338 is equivalent to about 200 mg of Loxo-338 free base, i.e., non-salt form.

[00088] In one preferred embodiment, the compound of Formula (I) is not a pharmaceutically acceptable salt, i.e., it is a free amine. [00089] The formulations disclosed herein are administered at least once daily. Alternatively, formulations disclosed herein are administered at least twice daily.

[00090] In one aspect, the inner portion can be made by a spray drying dispersion process.

[00091] In another aspect, the inner portion can be made by hot melt extrusion.

Cancers

[00092] The formulations disclosed herein may be used to treat disorders that respond to the inhibition of BCL2. Examples of treatable disorders include, but are not limited to hematological related disorders, e.g., hematological cancers such as those of the blood and bone marrow (leukemias, lymphomas and myelomas, with or without transformation, where applicable) amyloid light chain amyloidosis (AL amyloidosis) and post-transplant lymphoproliferative disorders (PTLD). Blood cell cancers are an example of hematological related disorders.

[00093] Hematologic related disorders also include rare genetic disorders, anemia, conditions related to HIV, sickle cell disease, and complications from chemotherapy or transfusions, including AL amyloidosis, and PTLD.

[00094] An example of disorders that can be treated using formulations containing the compound of Formula (I) and pharmaceutically acceptable salts thereof, include cancers that respond to the inhibition of BCL2. Examples of such cancers include breast cancer, prostate cancer, non-small cell lung cancer, hematological cancer, and others.

[00095] As used herein, the term “hematological cancer” refers to blood cell cancers such as non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), Waldenstrom macroglobulinemia (also referred to as Waldenstrom’s macroglobulinemia or Waldenstrom’s disease, abbreviated herein as “WM”), marginal zone lymphoma (MZL), follicular lymphoma (FL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL) (transformed, in particular Richter’s, or not), lymphoblastic lymphoma, lymphoblastic leukemia, prolymphocytic leukemia, Hodgkin’s disease, transformed low grade lymphoma, Burkitt lymphoma, or Burkitt like lymphoma.

[00096] As used herein, myeloma and multiple myeloma are used interchangeably.

[00097] In an aspect, disclosed are methods of treating a patient that has a disorder that responds to the inhibition of BCL2, the method comprising administering a therapeutically effective amount of a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one preferred embodiment, the formulation comprises a compound of Formula (I). In an embodiment, the disorder is hematological related disorder. In an embodiment, the hematological related disorders include rare genetic disorders, anemia, conditions related to HIV, sickle cell disease, and complications from chemotherapy or transfusions, including AL amyloidosis, or post-transplant lymphoproliferative disorders.

[00098] In another embodiment, the formulations disclosed herein may be used to treat hematological related disorders that are a blood cell cancer. In a further embodiment, the blood cell cancer is non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), Waldenstrom macroglobulin emi a (also referred to as Waldenstrom’s macroglobulinemia or Waldenstrom’s disease, abbreviated herein as “WM”), marginal zone lymphoma (MZL), follicular lymphoma (FL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL) (transformed, in particular Richter’s, or not), lymphoblastic lymphoma, lymphoblastic leukemia, prolymphocytic leukemia, Hodgkin’s disease, transformed low grade lymphoma, Burkitt lymphoma, or Burkitt like lymphoma.

[00099] In one embodiment, the formulations disclosed herein are used to treat chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), amyloid light chain amyloidosis (AL amyloidosis), mantle cell lymphoma (MCL), Waldenstrom macroglobulinemia (also referred to as Waldenstrom’s macroglobulinemia or Waldenstrom’s disease (WM). In an embodiment, the formulations disclosed herein are used to treat chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Or the formulations disclosed herein are used to treat amyloid light chain amyloidosis (AL amyloidosis). The formulations disclosed herein may be used to treat mantle cell lymphoma (MCL). The formulations disclosed herein may also be used to treat WM.

[000100] In an embodiment, the tablets described herein comprise about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, about 55 to about 61 wt % of at least one binder, about 2 to about 9 wt % of at least one surfactant, about 20 to about 27 wt % of at least one diluent or filler, about 0.5 to about 3 wt % glidant, and about 0.5 to about 2 wt % lubricant are used to treat chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In a further embodiment, pirtobrutinib or dexamethasone are also administered simultaneously, sequentially, or separately.

[000101] In one embodiment, tablets comprising about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, 55 to about 61 wt % copovidone, about % 2 to about 7 wt % sodium lauryl sulfate, about 20 to about 27 wt % mannitol, about 0.5 to about 3 wt % colloidal silicon dioxide, and about 0.2 to about 2 wt % sodium stearyl fumarate, are used to treat chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In a further embodiment, pirtobrutinib or dexamethasone are also administered simultaneously, sequentially, or separately.

[000102] In an embodiment, the tablets described herein comprise about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, about 55 to about 61 wt % of at least one binder, about 2 to about 9 wt % of at least one surfactant, about 20 to about 27 wt % of at least one diluent or filler, about 0.5 to about 3 wt % glidant, and about 0.5 to about 2 wt % lubricant are used to treat amyloid light chain amyloidosis (AL amyloidosis). In a further embodiment, pirtobrutinib or dexamethasone are also administered simultaneously, sequentially, or separately. [000103] In one embodiment, tablets comprising about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, 55 to about 61 wt % copovidone, about % 2 to about 7 wt % sodium lauryl sulfate, about 20 to about 27 wt % mannitol, about 0.5 to about 3 wt % colloidal silicon dioxide, and about 0.2 to about 2 wt % sodium stearyl fumarate, are used to treat amyloid light chain amyloidosis (AL amyloidosis). In a further embodiment, pirtobrutinib or dexamethasone are also administered simultaneously, sequentially, or separately.

[000104] In an embodiment, the tablets described herein comprise about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, about 55 to about 61 wt % of at least one binder, about 2 to about 9 wt % of at least one surfactant, about 20 to about 27 wt % of at least one diluent or filler, about 0.5 to about 3 wt % glidant, and about 0.5 to about 2 wt % lubricant are used to treat mantle cell lymphoma (MCL). In a further embodiment, pirtobrutinib or dexamethasone are also administered simultaneously, sequentially, or separately.

[000105] In one embodiment, tablets comprising about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, 55 to about 61 wt % copovidone, about % 2 to about 7 wt % sodium lauryl sulfate, about 20 to about 27 wt % mannitol, about 0.5 to about 3 wt % colloidal silicon dioxide, and about 0.2 to about 2 wt % sodium stearyl fumarate, are used to treat mantle cell lymphoma (MCL). In a further embodiment, pirtobrutinib or dexamethasone are also administered simultaneously, sequentially, or separately.

[000106] In an embodiment, the tablets described herein comprise about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, about 55 to about 61 wt % of at least one binder, about 2 to about 9 wt % of at least one surfactant, about 20 to about 27 wt % of at least one diluent or filler, about 0.5 to about 3 wt % glidant, and about 0.5 to about 2 wt % lubricant are used to treat Waldenstrom’s disease. In a further embodiment, pirtobrutinib or dexamethasone are also administered simultaneously, sequentially, or separately. [000107] In one embodiment, tablets comprising about 8 to about 15 wt % of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, 55 to about 61 wt % copovidone, about % 2 to about 7 wt % sodium lauryl sulfate, about 20 to about 27 wt % mannitol, about 0.5 to about 3 wt % colloidal silicon dioxide, and about 0.2 to about 2 wt % sodium stearyl fumarate, are used to treat Waldenstrom’s disease. In a further embodiment, pirtobrutinib or dexamethasone are also administered simultaneously, sequentially, or separately.

Treatment

[000108] The compound of Formula (I) or a pharmaceutically acceptable salt thereof may be used in a formulation as a first line treatment of one or more of the disorders described herein. First line treatment is understood to mean the cancer patient has not received prior therapy (they are treatment naive, with respect to the cancer). In one embodiment, the formulations disclosed herein are used to treat a disorder that is a hematological related disorder. Alternatively, the formulations disclosed herein are used to treat a disorder that is a hematological cancer.

[000109] Tn some embodiments, the formulations disclosed herein are used as monotherapy, i.e., they are not administered in conjunction with a second active pharmaceutical ingredient (API).

[000110] In other embodiments, the formulations disclosed herein are used in conjunction with one or more other APIs, wherein the formulation is administered with at least one other active pharmaceutical ingredient (API), simultaneously, sequentially, or separately. Examples of other APIs include BTK inhibitors (either covalent or non-covalent or reversible or irreversible), PI3K inhibitors, CDK 4/6 inhibitors, anti-CD20 antibody, steroids, and/or IDH inhibitors. Examples of BTK inhibitors include, but are not limited to pirtobrutinib, ibrutinib, acalabrutinib, tirabrutinib, zanubrutinib, orelabrutinib, nemtabrutinib (also known as ARQ 531 or MK-1026), GDC-0834, fenebrutinib (also known as GDC-0853), RN-486, CGI-1764, spebrutinib (also known as CC-292), and CNX-774. Examples of PI3K inhibitors include, but are not limited to regorafenib, idelalisib, copanlisib HC1, duvelisib, alpelisib, umbralisib tosylate, linperlisib, zandelisib, inavolisib (also known as GDC- 0077), eganelisib, pictilisib, LY3849524 and parsaclisib. Examples of CDK 4/6 inhibitors include, but are not limited to palbociclib, ribociclib, abemaciclib, trilaciclib, G1T28, G1T38, AMG 925, SHR-6390, BPI-1178, BPI-16350, FCN 437, birociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K. Examples of anti-CD20 antibodies include, but are not limited to, rituximab and obinutuzumab. Examples of steroids that could be used include dexamethasone, prednisolone, and prednisone. Examples of IDH inhibitors include, but are not limited to ivosidenib, enasidenib, vorasidenib, olutasidenib, GSK864, AGI-6780, AGI-5198, AGI-12026, IDH-305, IDH889, BAY-1436032, safusidenib, and LY3410738. When the formulations disclosed herein are administered in combination with one or more other APIs, the formulations and the APIs may be administered sequentially or simultaneously.

[000111] Additional examples of other APIs include histone deactylases (HDACs) and hypomethylating agents (HMAs). Examples of HDACs include, but are not limited to Panobinostat, vorinostat, romidepsin, FK-A5, FK-A1 1 , nexturastat A, RGFP966, ricolinostat, citarinostat, entinostat, tucidinostat (also known as chidomide), CUDC-101, abexinostat, belinostat, valproic acid and sodium phenylbutyrate. Examples of HMAs include, but are not limited to, cytidine and 5- azadeoxycytidine analogs (e.g., 5-azacitidine decitabine, cladribine, zebularine), procainamide, procaine, hydralazine, epigallocathechin-3- gallate, RG108, MG98, and a thioguanine.

[000112] The compound of Formula (I) or a pharmaceutically acceptable salt thereof may be used in a formulation to treat one or more of the disorders described herein, after the cancer patient has received prior therapy. In one embodiment, the formulations disclosed herein are used to treat a disorder that is a hematological related disorder. Alternatively, the formulations disclosed herein are used to treat a disorder that is a hematological cancer. In some embodiments, the formulations disclosed herein are used after the patient has received prior therapy, as monotherapy, i.e., they are not administered in conjunction with a second active pharmaceutical ingredient (API). In other embodiments, the formulations disclosed herein are used in conjunction with one or more other APIs, after the patient has received prior therapy. Examples of other APIs include BTK inhibitors (either covalent or non-covalent or reversible or irreversible), PI3K inhibitors, CDK 4/6 inhibitors, anti-CD20 antibody, and/or IDH inhibitors.

[000113] Examples of BTK inhibitors include, but are not limited to pirtobrutinib, ibrutinib, acalabrutinib, tirabrutinib, zanubrutinib, orelabrutinib, nemtabrutinib (also known as ARQ 531 or MK-1026), GDC-0834, fenebrutinib (also known as GDC- 0853), RN-486, CGI- 1764, spebrutinib (also known as CC-292), and CNX-774. Examples of PI3K inhibitors include, but are not limited to regorafenib, idelalisib, copanlisib HC1, duvelisib, alpelisib, umbralisib tosylate, linperlisib, zandelisib, inavolisib (also known as GDC-0077), eganelisib, pictilisib, LY3849524 and parsaclisib. Examples of CDK 4/6 inhibitors include, but are not limited to palbociclib, ribociclib, abemaciclib, trilaciclib, G1T28, G1T38, AMG 925, SHR- 6390, BPT-1 178, BPT-16350, FCN 437, birociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K. Examples of anti-CD20 antibodies include, but are not limited to rituximab and obinutuzumab. Examples of IDH inhibitors include, but are not limited to ivosidenib, enasidenib, vorasidenib, olutasidenib, GSK864, AGI-6780, AGI-5198, AGI- 12026, IDH-305, IDH889, BAY- 1436032, safusidenib, and LY3410738. When the formulations disclosed herein are administered in combination with one or more other APIs, the formulations and the APIs may be administered simultaneously, sequentially, or separately.

[000114] In one embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is simultaneously, separately, or sequentially administered with a BTK inhibitor. In one embodiment, the BTK inhibitor is pirtobrutinib or a pharmaceutically acceptable salt thereof. In one embodiment, pirtobrutinib is administered for at least one 28-day cycle prior to administering BCL2-I or a pharmaceutically acceptable salt thereof. In one embodiment, the patient is treatment naive. In one embodiment, the patient had one or more prior lines of therapy. In one embodiment, the patient had two or more prior lines of therapy. In one embodiment, the patient is administered a daily dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is between about 25 mg/day and about 400 mg/day, or about 50 mg/day and 350 mg/day, or about 100 mg/day and 300 mg/day, or about 200 mg/day and 400 mg/day. In one embodiment, the daily dose is about 25 mg/day. In one embodiment, the daily dose is about 50 mg/day. In one embodiment, the daily dose is about 100 mg/day. In one embodiment, the daily dose is about 150 mg/day. In one embodiment, the daily dose is about 200 mg/day. In one embodiment, the daily dose is about 250 mg/day. In one embodiment, the daily dose is about 300 mg/day. In one embodiment, the daily dose is about 350 mg/day. In one embodiment, the daily dose is about 400 mg/day. In one embodiment the compound is the compound of Formula (I) and the BTK inhibitor is pirtobrutinib. The dose of the compound of Formula (I) may comprise at least one 25 mg tablet. The dose of the compound of Formula (I) may comprise at least one 50 mg tablet. The dose of the compound of Formula (I) may comprise at least one 100 mg tablet.

[000115] The daily doses described herein may be administered using a variety of different sized formulations. For example, if 300 mg of the compound of Formula (I) is to be administered, it is possible to administer six 50 mg tablets, three 100 mg tablets, or two 50 mg tablets and two 100 mg tablets. Other combinations of pill sizes may be used, as is readily apparent.

[000116] The compound of Formula (I) or a pharmaceutically acceptable salt thereof, is simultaneously, separately, or sequentially administered with a steroid. In an embodiment, the steroid is dexamethasone. In one aspect, dexamethasone is administered at 20 mg weekly. In one embodiment, dexamethasone may be given on a single day. In one embodiment, dexamethasone may be given in a divided dose over 2 days. In one embodiment, for patients who are > 75 years of age, underweight (body mass index < 19), have hypervolemia, poorly controlled diabetes mellitus, or prior intolerance/adverse event to steroid therapy, the total dexamethasone dose may be reduced at the discretion of the Physician.

[000117] In another embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is simultaneously, separately, or sequentially administered with prednisone. The prednisone is dosed orally at 5 to 60 mg per day. The daily dose may be administered in a single dose or two or more doses.

[000118] In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is simultaneously, separately, or sequentially administered with prednisolone. The prednisone is dosed orally at 5 to 200 mg per day. The daily dose may be administered in a single dose or two or more doses. At a medical doctor’s discretion, a larger, initial dose (e.g. 200 mg) may be used, followed by lower doses (for example, 80 mg orally, every other day).

[000119] The compound of Formula (I) or pharmaceutically acceptable salts thereof, may be amorphous, crystalline or a mixture thereof. If the compound of Formula (I) or pharmaceutically acceptable salt thereof is spray dried, the compound of Formula (I) or pharmaceutically acceptable salt thereof will be amorphous.

[000120] In one preferred embodiment, the compound of Formula (I) is formulated as a spray dried dispersion. When the tablet comprises an inner portion that is spray dried, the inner portion does not contain silicon dioxide.

Uses

[000121] Provided herein is the compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder that responds to the inhibition of BCL2, as described herein.

[000122] In an embodiment, the use is to treat a disorder that is a hematological related disorder. In particular, the hematological related disorder is a hematological cancer. In one aspect, the treatment is in a patient who is treatment naive. In one aspect, the treatment is in a patient who has had one or more prior lines of therapy. In one aspect, the treatment is in a patient who has had two or more prior lines of therapy. In one aspect, the treatment comprises the administration of a daily dose of BCL2-I or a pharmaceutically acceptable salt thereof, and the daily dose is between about 25 mg/day and about 400 mg/day, or about 50 mg/day and 350 mg/day, or about 100 mg/day and 300 mg/day, or about 200 mg/day and 400 mg/day. In one aspect, the daily dose is about 25 mg/day. In one aspect, the daily dose is about 50 mg/day. In one aspect, the daily dose is about 100 mg/day. In one aspect, the daily dose is about 150 mg/day. In one aspect, the daily dose is about 200 mg/day. In one aspect, the daily dose is about 250 mg/day. In one aspect, the daily dose is about 300 mg/day. In one aspect, the daily dose is about 350 mg/day. In one aspect, the daily dose is about 400 mg/day.

Processes

[000123] The tablet formulations described herein, comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof are prepared/obtainable by spray drying a mixture (if not everything dissolves) or a solution (if everything dissolves) comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[000124] The tablet formulations described herein, comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof are prepared/obtainable by spray drying a mixture (if not everything dissolves) or a solution (if everything dissolves) comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the mixture or solution comprises acetone and water. In a preferred embodiment, a solution is formed and then spray dried. If a mixture is spray dried, processing difficulties may result. An example of a difficulty is the clogging of the spray dry nozzle by the undissolved solids.

[000125] The tablet formulations described herein, comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof are prepared/obtainable by spray drying a comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the solution comprises acetone and water.

[000126] The tablet formulations described herein, comprising a compound of Formula (I) are prepared/obtainable by spray drying a mixture (if not everything dissolves) or a solution (if everything dissolves) comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In a preferred embodiment, a solution is formed and then spray dried. If a mixture is spray dried, processing difficulties may result.

[000127] The tablet formulations described herein, comprising a compound of Formula (I) are prepared/obtainable by spray drying a mixture (if not everything dissolves) or a solution (if everything dissolves) comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the solvent mixture or solution comprises acetone and water. In a preferred embodiment, a solution is formed and then spray dried. If a mixture is spray dried, processing difficulties may result.

[000128] The tablet formulations described herein, comprising a compound of Formula (I) are prepared/obtainable by spray drying a solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the solution comprises acetone and water.

[000129] In an embodiment, the mixture or solution comprises about 95:5 or about 90: 10 or about 80:20 or about 70:30, or about 60:40 parts acetone to about 10 parts water. In one preferred embodiment, the solution is made using about 90: 10 acetone: water.

[000130] In an embodiment, the at least one pharmaceutically acceptable excipient comprises a surfactant. In one preferred embodiment, the surfactant comprises sodium lauryl sulfate. [000131] In an embodiment, the at least on pharmaceutically acceptable excipient comprises a binder. In one preferred embodiment, the binder comprises copovidone. In an alternate embodiment, the binder comprises povidone.

[000132] In an embodiment, the at least on pharmaceutically acceptable excipient comprises a surfactant and a binder. In an embodiment, the surfactant comprises sodium lauryl sulfate, and the binder comprises copovidone or povidone. In a further embodiment, the surfactant comprises sodium lauryl sulfate, and the binder comprises povidone. In a further embodiment, the surfactant comprises sodium lauryl sulfate, and the binder comprises copovidone.

[000133] After spray drying the compound of Formula (I) and any pharmaceutically acceptable excipients, the resulting spray dried dispersion is mixed with other pharmaceutically acceptable excipients, further processed - if necessary, and then compressed to form a tablet. The tablet may be of any size or shape. The tablet is then optionally coated with a pharmaceutically acceptable coating, such as Opadry white.

Examples

Example 1

[000134] The compound of Formula (I), copovidone and sodium lauryl sulfate were dissolved in acetone:water (9: 1) and then spray dried using a PSD2 spray drier made by GEA Niro. Residual solvent was then removed from the spray dried mixture.

Example 2

[000135] 10 mg, 25 mg and 100 mg tablets containing Loxo-338 were prepared, using the method of Example 1. The solids content in the spray solution was about 7%, by weight, i.e., compound plus povidone plus SLS is about 7% by weight of the spray solution, whereas the remaining 93 weight % is acetone and water (90: 10). Roller compaction was used to prepare intragranular material. Extragranular excipients were added after collection of the milled ribbons, which contain the spray dried dispersion and the intragranular portion.

Example 3

The parameters used in the spray drying process are defined below. This example prepares the inner portion, i.e., spray dried portion, of the tablet.

* Weight %; Plasdone S630 is copovidone; SLS is sodium lauryl sulfate

Example 4 pH solubility comparison between API (Loxo-338) and the spray dried dispersion made according to Example 3.

Concentrations are in micrograms/ml; SIF is simulated intestinal fluid powder; SLS is sodium lauryl sulfate; PBS is phosphate buffered saline

[000136] The above table demonstrates the Loxo-338 in the spray dried dispersion is significantly more soluble than non-spray dried Loxo-338.

Example 5

The properties of some particles made using the spray dried dispersion protocol described in Example 3.

XRD is x-ray diffraction; SEM is scanning electron microscope; KF is Karl Fischer

Example 6

The properties of one batch of (10/25/100 mg) tablets

The disintegration times were measured in dissolution media - pH 6.5 phosphate buffer with 1% SLS. A type II USP apparatus set to 75 RPM paddle speed was used. Additional Embodiments

Embodiment 1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder that responds to the inhibition of BCL2.

Embodiment 2. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 1, wherein the disorder is hematological related disorders.

Embodiment 3. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 2, wherein the hematological related disorders is rare genetic disorders, anemia, conditions related to HIV, sickle cell disease, and complications from chemotherapy or transfusions, including AL amyloidosis, or post-transplant lymphoproliferative disorders.

Embodiment 4. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 2, wherein the hematological related disorders is a blood cell cancer.

Embodiment 5. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 4, wherein the blood cell cancer is non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), Waldenstrom macroglobulinemia (also referred to as Waldenstrom’s macroglobulinemia or Waldenstrom’s disease, abbreviated herein as “WM”), marginal zone lymphoma (MZL), follicular lymphoma (FL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL) (transformed, in particular Richter’s, or not), lymphoblastic lymphoma, lymphoblastic leukemia, prolymphocytic leukemia, Hodgkin’s disease, transformed low grade lymphoma, Burkitt lymphoma, or Burkitt like lymphoma.

Embodiment 6. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 1, wherein the disorder is Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), amyloid light chain amyloidosis (AL amyloidosis), mantle cell lymphoma (MCL), Waldenstrom macroglobulinemia (also referred to as Waldenstrom’s macroglobulinemia or Waldenstrom’s disease (WM).

Embodiment 7. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 1 or 6, wherein the disorder is chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Embodiment 8. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 1 or 6, wherein the disorder is amyloid light chain amyloidosis (AL amyloidosis).

Embodiment 9. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 1 or 6, wherein the disorder is mantle cell lymphoma (MCL).

Embodiment 10. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 1 or 6, wherein the disorder is Waldenstrom’s disease (WM).

Embodiment 11. The compound or pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1-10, wherein the formulation is administered at least once daily.

Embodiment 12. The compound or pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1-10, wherein the formulation is administered at least twice daily.

Embodiment 13. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments 1-12, for use in simultaneous, separate or sequential combination with at least one other active pharmaceutical ingredient (API).

Embodiment 14. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 13, wherein the API comprises at least one of BTK inhibitors (either covalent or non-covalent or reversible or irreversible), PI3K inhibitors, CDK 4/6 inhibitors, anti-CD20 antibody, steroids, and/or IDH inhibitors.

Embodiment 15. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 13, wherein the API comprises histone deactylases (HDACs) and hypomethylating agents (HMAs).

Embodiment 16. The compound or pharmaceutically acceptable salt thereof for use according to any one of Embodiments 13-14, wherein the API is dexamethasone.

Embodiment 17. The compound or pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1-16, wherein the patient has received prior therapy.

Embodiment 18. The compound or pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1-16, wherein the patient has not received prior therapy.

Embodiment 19. The compound or pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1-18, wherein the patient is administered a therapeutically effective amount of a compound of Formula (I).

Embodiment 20. The compound or pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1-19, wherein the formulation is as described in claims 1-45 or 72-73.

Embodiment 21. A pharmaceutical formulation comprising a compound of

Formula (I)

or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Embodiment 22. The pharmaceutical formulation according to Embodiment 21, wherein the excipient comprises at least one of diluents or fillers, binders, granulating agents, adhesives, polymers and copolymers, disintegrants, stabilizers, lubricants, anti -adherents, glidants, surfactants, dispersing or wetting agents, dissolution retardants or enhancers, adsorbents, buffers, chelating agents, preservatives, colors, flavors, sweeteners, or combinations of two or more thereof.

Embodiment 23. The pharmaceutical formulation according to any one of Embodiments 21-22, wherein the formulation is a tablet.

Embodiment 24. The pharmaceutical formulation according to Embodiment 23, wherein the tablet comprises an inner portion, an intragranular portion and an extragranular portion.

Embodiment 25. The pharmaceutical formulation according to Embodiment 24, wherein the inner portion comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Embodiment 26. The pharmaceutical formulation according to Embodiment 25, wherein the inner portion further comprises at least one binder.

Embodiment 27. The pharmaceutical formulation according to Embodiments 24-

26, wherein the inner portion further comprises at least one lubricant.

Embodiment 28. The pharmaceutical formulation according to Embodiments 24-

27, wherein the binder comprises copovidone.

Embodiment 29. The pharmaceutical formulation according to Embodiments 24-

28, wherein the inner portion comprises a surfactant and the surfactant comprises sodium lauryl sulfate.

Embodiment 30. The pharmaceutical formulation according to any one of Embodiments 24-29, wherein the intragranular portion comprises at least one diluent or filler.

Embodiment 31. The pharmaceutical formulation according to any one of Embodiments 24-30, wherein the intragranular portion comprises at least one glidant. Embodiment 32. The pharmaceutical formulation according to any one of Embodiments 24-31, wherein the intragranular portion comprises at least one surfactant.

Embodiment 33. The pharmaceutical formulation according to any one of Embodiment 30, wherein the diluent or filler in the intragranular portion comprises mannitol.

Embodiment 34. The pharmaceutical formulation according to any one of Embodiment 31, wherein the glidant in the intragranular portion comprises colloidal silicon dioxide.

Embodiment 35. The pharmaceutical formulation according to any one of Embodiment 27, wherein the lubricant in the intragranular portion comprises sodium stearyl fumarate.

Embodiment 36. The pharmaceutical formulation according to any one of Embodiments 24-35, wherein the extragranular portion comprises at least one surfactant.

Embodiment 37. The pharmaceutical formulation according to any one of Embodiments 24-36, wherein the extragranular portion comprises a lubricant in the and the lubricant comprises sodium stearyl fumarate.

Embodiment 38. The pharmaceutical formulation according to any one of Embodiments 24-37, wherein the inner portion comprises about 10 mg of the compound of Formula (I).

Embodiment 39. The pharmaceutical formulation according to any one of Embodiments 24-37, wherein the inner portion comprises about 25 mg of the compound of F omul a (I).

Embodiment 40. The pharmaceutical formulation according to any one of Embodiments 24-37, wherein the inner portion comprises about 100 mg of the compound of Formula (I).

Embodiment 41. The pharmaceutical formulation according to any one of Embodiments 24-40, wherein the inner portion comprises about 10 to about 13 wt % of the compound of Formula (I). Embodiment 42. The pharmaceutical formulation according to any one of Embodiments 24-39, wherein the inner portion comprises about 45 to about 65 wt % of at least one binder.

Embodiment 43. The pharmaceutical formulation according to any one of Embodiments 24-42, wherein the inner portion comprises about 50 to about 60 wt % of at least one binder.

Embodiment 44. The pharmaceutical formulation according to any one of Embodiments 24-43, wherein the inner portion comprises about 1 to about 8 wt % of at least one lubricant.

Embodiment 45. The pharmaceutical formulation according to any one of Embodiments 24-44, wherein the inner portion comprises about 2 to about 6 wt % of at least one lubricant.

Embodiment 46. The pharmaceutical formulation according to any one of Embodiments 24-45, wherein the intragranular portion comprises about 15 to about 35 wt % of at least one diluent or filler.

Embodiment 47. The pharmaceutical formulation according to any one of Embodiments 24-46, wherein the intragranular portion comprises about 20 to about 30 wt % of at least one diluent or filler.

Embodiment 48. The pharmaceutical formulation according to any one of Embodiments 24-47, wherein the intragranular portion comprises about 0.1 to about 3 wt % of at least one glidant.

Embodiment 49. The pharmaceutical formulation according to any one of Embodiments 24-48, wherein the intragranular portion comprises about 0.5 to about 2 wt % of at least one glidant.

Embodiment 50. The pharmaceutical formulation according to any one of Embodiments 24-49, wherein the intragranular portion comprises about 0.1 to about 3 wt % of at least one surfactant. Embodiment 51. The pharmaceutical formulation according to any one of Embodiments 24-50, wherein the intragranular portion comprises about 0.2 to about 2 wt % of at least one surfactant.

Embodiment 52. The pharmaceutical formulation according to any one of Embodiments 24-51, wherein the extragranular portion comprises about 0.1 to about 4 wt % of at least one surfactant.

Embodiment 53. The pharmaceutical formulation according to any one of Embodiments 24-52, wherein the extragranular portion comprises about 0.2 to about 2 wt % of at least one surfactant.

Embodiment 54. A pharmaceutical formulation comprising the compound of Formula (I),

or a pharmaceutically acceptable salt thereof, copovidone, sodium lauryl sulfate, mannitol, colloidal silicon dioxide, and sodium stearyl fumarate.

Embodiment 55. The formulation according to Embodiment 54, wherein the formulation is a tablet.

Embodiment 56. The formulation according to Embodiment 55, wherein the tablet comprises about 8 to about 15 wt % of the compound of Formula (I).

Embodiment 57. The formulation according to any one of Embodiments 54-56, wherein the tablet further comprises about 55 to about 61 wt % copovidone.

Embodiment 58. The formulation according to any one of Embodiments 54-57, wherein the tablet further comprises about 2 to about 7 wt % sodium lauryl sulfate. Embodiment 59. The formulation according to any one of Embodiments 54-58, wherein the tablet further comprises about 20 to about 27 wt % mannitol.

Embodiment 60. The formulation according to any one of Embodiments 54-59, wherein the tablet further comprises about 0.5 to about 3 wt % colloidal silicon dioxide.

Embodiment 61. The formulation according to any one of Embodiments 54-60, wherein the tablet further comprises about 0.2 to about 2 wt % sodium stearyl fumarate.

Embodiment 62. The formulation according to any one of Embodiments 54 to 61, wherein the tablet comprises about 10 mg of the compound of Formula (I).

Embodiment 63. The formulation according to any one of Embodiments 54 to 61, wherein the tablet comprises about 25 mg of the compound of Formula (I).

Embodiment 64. The formulation according to any one of Embodiments 54 to 61, wherein the tablet comprises about 100 mg of the compound of Formula (I).

Embodiment 65. The formulation according to any one of Embodiments 21 to 64, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is contained in a spray dried dispersion.

Embodiment 66. A tablet formulation according to Embodiment 24, wherein the inner portion comprises the compound of Formula (T), copovidone, and sodium lauryl sulfate; the intra granular portion comprises mannitol, colloidal silicon dioxide, and sodium stearyl fumarate; and the extragranular portion comprises sodium stearyl fumarate.

Embodiment 67. A tablet formulation according to Embodiment 24 or 66, wherein the inner portion comprises about 11 wt % of the compound of Formula (I), about 58 wt % copovidone, and about 4.6 wt % sodium lauryl sulfate; the intra granular portion comprises about 23 wt % mannitol, about 1.1 wt % colloidal silicon dioxide, and about 0.6 wt % sodium stearyl fumarate; and the extragranular portion comprises about 0.6 wt % sodium stearyl fumarate, wherein the wt % are based on the total weight of the tablet.

Embodiment 68. A process for preparing a formulation comprising a compound of Formula (I)

Embodiment 69. The process according to Embodiment 68, wherein the solution comprises about 90 parts acetone to about 10 parts water.

Embodiment 70. The process according to any one of Embodiments 68-69, wherein the at least one pharmaceutically acceptable excipient comprises a surfactant.

Embodiment 71. The process according to Embodiment 70, wherein the surfactant comprises sodium lauryl sulfate.

Embodiment 72. The process according to any one of Embodiments 68-71, wherein the at least one pharmaceutically acceptable excipient comprises a binder.

Embodiment 73. The process according to claim 72, wherein the binder comprises copovidone.

Claims

Claims We claim:

1. A pharmaceutical formulation comprising a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the excipient comprises at least one of diluents or fillers, binders, granulating agents, adhesives, polymers and copolymers, disintegrants, stabilizers, lubricants, anti-adherents, glidants, surfactants, dispersing or wetting agents, dissolution retardants or enhancers, adsorbents, buffers, chelating agents, preservatives, colors, flavors, sweeteners, or combinations of two or more thereof.

2. The pharmaceutical formulation according to claim 1, wherein the formulation is a tablet, and the tablet comprises an inner portion, an intragranular portion and an extragranular portion.

3. The pharmaceutical formulation according to claim 2, wherein the inner portion comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical formulation according to claim 3, wherein the inner portion further comprises at least one binder.

5. The pharmaceutical formulation according to claims 3-4, wherein the inner portion further comprises at least one lubricant.

6. The pharmaceutical formulation according to claim 5, wherein the binder comprises copovidone and the surfactant comprises sodium lauryl sulfate.

7. The pharmaceutical formulation according to any one of claims 3-6, wherein the intragranular portion comprises at least one diluent or filler.

8. The pharmaceutical formulation according to any one of claims 3-7, wherein the intragranular portion comprises at least one glidant.

9. The pharmaceutical formulation according to any one of claims 3-8, wherein the intragranular portion comprises at least one surfactant.

10. The pharmaceutical formulation according to claim 7, wherein the diluent or filler in the intragranular portion comprises mannitol.

11. The pharmaceutical formulation according to claim 8, wherein the glidant in the intragranular portion comprises colloidal silicon dioxide.

12. The pharmaceutical formulation according to claim 5, wherein the lubricant in the intragranular portion comprises sodium stearyl fumarate.

13. The pharmaceutical formulation according to any one of claims 3-12, wherein the extragranular portion comprises at least one surfactant.

14. The pharmaceutical formulation according to any one of claims 3-13, wherein the extragranular portion comprises a lubricant, and the lubricant comprises sodium stearyl fumarate.

15. The pharmaceutical formulation according to any one of claims 3-14, wherein the inner portion comprises about 25 mg or about 100 mg of the compound of Formula (I).

16. A pharmaceutical formulation comprising the compound of Formula (I),

17. The formulation according to claim 16, wherein the formulation is a tablet and the tablet comprises about 8 to about 15 wt % of the compound of Formula (I), about 55 to about 61 wt % copovidone, about 2 to about 7 wt % sodium lauryl sulfate, about 20 to about 27 wt % mannitol, about 0.5 to about 3 wt % colloidal silicon dioxide, and about 0.2 to about 2 wt % sodium stearyl fumarate.

18. The formulation according to any one of claims 1 to 17, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is contained in a spray dried dispersion.

19. A formulation comprising a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein the formulation is obtainable by spray drying a solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and combining the spray dried compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the solution comprises acetone and water.

20. The tablet formulation according to claim 2, wherein the inner portion comprises the compound of Formula (I), copovidone, and sodium lauryl sulfate; the intra granular portion comprises mannitol, colloidal silicon dioxide, and sodium stearyl fumarate; and the extragranular portion comprises sodium stearyl fumarate.

21. The tablet formulation according to claim 20, wherein the inner portion comprises about 11 wt % of the compound of Formula (I), about 58 wt % copovidone, and about 4.6 wt % sodium lauryl sulfate; the intra granular portion comprises about 23 wt % mannitol, about 1.1 wt % colloidal silicon dioxide, and about 0.6 wt % sodium stearyl fumarate; and the extragranular portion comprises about 0.6 wt % sodium stearyl fumarate, wherein the wt % are based on the total weight of the tablet.

22. A method of preparing a formulation comprising a compound of formula:

or a pharmaceutically acceptable salt thereof, the method comprising: