BR112017021325B1 - COMPOSITIONS CONTAINING IBRUTINIB, THEIR PREPARATION PROCESS AND USE - Google Patents

Abstract

COMPOSITIONS CONTAINING IBRUTINIB, THEIR PREPARATION PROCESS AND USE. The present invention relates to pharmaceutical compositions containing Ibrutinib and processes for preparing the same. The compositions can be used in the treatment of a variety of conditions including, but not limited to, B-cell proliferative diseases such as non-Hodgkin's lymphoma (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma or Burkitt), Waldenstrom's macroglobulinemia, plasma cell myeloma, chronic lymphocytic leukemia, lymphoma or leukemia. Such compositions are intended for oral ingestion. The compositions are contained within a capsule, as a standard or dispersible or in a liquid formulation or as a suspension. In one embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. In another embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide and water.

Description

TECHNICAL FIELD

[0001] This invention relates to compositions containing Ibrutinib and methods for their use,

BACKGROUND

[0002] Targeted therapy involves identifying specific differences between cancer cells and normal cells, These differences are used to create a targeted therapy to attack cancer cells without harming normal cells, thus causing fewer side effects, There are differences between the various types of targeted therapy, but all interfere with the cancer cell's ability to grow, divide, repair itself, and/or communicate with other cells,

[0003] Ibrutinib is an anticancer drug that targets B cell malignancies, Ibrutinib blocks the signals that encourage malignant B cells to grow and divide uncontrollably, It was approved by the US FDA in November 2013 for the treatment of mantle cell lymphoma and, in February 2014, for the treatment of chronic lymphocytic leukemia, It is a selective and covalent inhibitor (ICs0=0.46 nm) of Bruton's tyrosine kinase enzyme (BTK) via covalent to the cysteine residue Cys-481 in the active site of BTK, administered orally, BTK is a signaling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways, The BCR pathway is involved in various B-cell malignancies, including B-cell CML and CLL, Ibrutinib is marketed in the US as an oral capsule (Imbruvica™),

[0004] What is needed in the art are alternative formulations containing Ibrutinib,

SUMMARY OF THE INVENTION

[0005] In one aspect, pharmaceutical compositions are provided comprising Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. In one embodiment, the composition contains from about 40 to about 45% by weight of Ibrutinib.

[0006] In another aspect, pharmaceutical compositions are provided comprising (i) from about 40 to about 45% by weight of Ibrutinib; (ii) from about 44 to about 47% by weight of microcrystalline cellulose; (iii) from about 6 to about 8% by weight of croscarmellose sodium; (iv) from about 1 to about 5% by weight of sodium lauryl sulfate; and (v) from about 0.2 to about 0.3% by weight magnesium stearate.

[0007] In another aspect, pharmaceutical compositions are provided comprising (i) about 140 mg of Ibrutinib; (ii) about 151 mg of microcrystalline cellulose; (iii) about 23 mg of croscarmellose sodium; (iv) about 14 mg of sodium lauryl sulfate; and (v) about 1.6 mg of magnesium stearate.

[0008] In yet another aspect, pharmaceutical compositions are provided comprising (i) about 50 mg of Ibrutinib; (ii) about 54 mg of microcrystalline cellulose; (iii) about 8 mg of croscarmellose sodium; (iv) about 5 mg of sodium lauryl sulfate; and (v) about 0.6 mg of magnesium stearate.

[0009] In yet another aspect, capsules or sachets are provided which comprise at least one of the pharmaceutical compositions described herein. In certain embodiments, the capsule is of the standard or dispersible type.

[0010] In another aspect, pharmaceutical compositions are provided comprising Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide and water.

[0011] In yet another aspect, pharmaceutical compositions are provided comprising (i) about 70 mg/ml of Ibrutinib; (ii) about 13 mg/ml of a combination of microcrystalline cellulose and sodium carboxymethylcellulose; (iii) about 2.5 mg/ml of hydroxypropyl methylcellulose; (iv) about 1.5 mg/ml citric acid monohydrate; (v) about 1.4 mg/ml of disodium hydrogen phosphate; (vi) about 1 mg/ml of sucralose; (vii) about 1 mg/ml sodium methyl parahydroxybenzoate; and (viii) about 0.6 mg/ml sodium ethyl parahydroxybenzoate.

[0012] In other aspects, pharmaceutical compositions are provided comprising (i) about 40 mg/ml of Ibrutinib; (ii) about 14 mg/ml of a combination of microcrystalline cellulose and sodium carboxymethylcellulose; (iii) about 1 mg/ml of hydroxypropyl methylcellulose; (iv) about 1.5 mg/ml citric acid monohydrate; (v) about 1.4 mg/ml of disodium hydrogen phosphate; (vi) about 0.5 mg/ml sucralose; (vii) about 1.4 mg/ml sodium methyl parahydroxybenzoate; and (viii) about 0.6 mg/ml sodium ethyl parahydroxybenzoate.

[0013] In yet another aspect, methods are provided for treating a B-cell proliferative disease, comprising the steps of administering at least one pharmaceutical composition described herein to an individual in need thereof. In certain embodiments, the B-cell proliferative disease is non-Hodgkin's lymphoma, Waldentron's macroglobulinemia, plasma cell myeloma, or chronic lymphocytic leukemia.

[0014] In a further aspect, methods are provided for treating a lymphoma comprising administering at least one composition described herein to an individual in need thereof.

[0015] In another aspect, methods are provided for treating a leukemia comprising administering at least one composition described herein to an individual in need thereof.

[0016] In yet another aspect, methods are provided for treating mantle cell lymphoma in a subject who has already received at least one prior therapy for mantle cell lymphoma, comprising administering at least one composition herein described to the individual once a day.

[0017] In a further aspect, the treatment methods of the present invention involve the use of a dispersible capsule which is opened to facilitate dispersion of the capsule contents in the food or beverage. In one embodiment, the beverage is water. In another embodiment, the food is a soft food. The contents of the capsule can also be administered through a feeding tube after using a suitable vehicle such as water, milk or other common beverages. It should be noted that the suspension formulation can also be administered via a feeding tube.

[0018] In yet another aspect, processes are provided for preparing the compositions described herein, comprising, (a) mixing microcrystalline cellulose, a first portion of sodium lauryl sulfate and a first portion of croscarmellose sodium; (b) mixing the product of step (a) with a first portion of Ibrutinib; (c) mixing the product of step (b) with a second portion of Ibrutinib; (d) mixing the product of step (c) with a first portion of magnesium stearate; (e) roller compacting the product of step (d); (f) milling the tapes produced in step (e); (g) mixing the granules produced in step (e) with a second portion of sodium lauryl sulfate and sodium croscarmellose; and (h) mixing the product of step (g) with a second portion of magnesium stearate. In one embodiment, the process further includes (i) adding the product of step (h) to a capsule.

[0019] In a further aspect, processes are provided for preparing the compositions described herein, comprising (a) mixing water, microcrystalline cellulose and croscarmellose sodium; (b) mixing water with hydroxypropyl methylcellulose; (c) mixing the product of step (b) with Ibrutinib; (d) mixing the product of steps (a) and (c); (e) mixing the product of step (d) with sucralose; (f) mixing the product of step (e) with sodium methyl parahydroxybenzoate and sodium ethyl parahydroxybenzoate; (g) mixing the product of step (f) with the citric acid monohydrate; and (h) mixing the product of step (g) with anhydrous disodium hydrogen phosphate. In one embodiment, the process further includes (i) adjusting the pH of the product of step (h) to a pH of about 6. In another embodiment, the process further includes adding water to the product of step (h) or (i ). In another aspect, the processes further include adding the composition to a vial.

[0020] Other aspects and advantages of the present invention are further described in the following detailed description of preferred embodiments thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The present application is better understood when read in conjunction with the attached drawings. With the purpose of illustrating the subject, the exemplifying modalities of the subject are shown in the drawings; however, the subject matter disclosed herein is not limited to the specific compositions, methods, devices and systems disclosed. Furthermore, the drawings are not necessarily put to scale.

[0022] Figure 1 provides a process flow diagram for preparing capsules containing Ibrutinib.

[0023] Figure 2 provides a process flow diagram for preparing liquid formulations containing Ibrutinib.

[0024] Figure 3 provides a process flow diagram for the large-scale preparation of a liquid formulation containing Ibrutinib.

DETAILED DESCRIPTION OF ILLUSTRATIVE MODALITIES

[0025] The present invention may be more readily understood by reference to the following detailed description taken in conjunction with the accompanying figures and examples, all of which form part of this disclosure. It is to be understood that this invention is not limited to the specific products, methods, conditions or parameters described and/or shown herein, and that the terminology used in the present invention is intended to describe specific embodiments by way of example only and is not intended to limit any claimed invention. Similarly, except where otherwise specified, any description of a possible mechanism or mode of action or reason for improvement is intended to be illustrative only, and the present invention is not to be restricted by accuracy or inaccuracy or any mechanism or mode of Suggested action or reason for improvement. Throughout the description, it is recognized that the descriptions relate to both the resources and the methods for producing and using the compositions described herein.

[0026] In the present description the singular forms "a", "the", "a" and "a" include reference in the plural, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicate otherwise. Thus, for example, a reference to "a material" is a reference to at least one or more of those materials and their equivalents known to those skilled in the art, and so on.

[0027] When values are expressed as approximations by using the descriptor "about" or "substantially", it should be understood that the specific value forms another modality. In general, the use of the term "about" or "substantially" indicates approximations that may vary depending on the desired properties sought to be achieved by the subject disclosed and should be interpreted in the specific context in which it is used, based on its function. One skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a specific value can be a non-limiting method of determining the length of the word "about" or "substantially". In other cases, the gradations used in a series of values can be used to determine the intended range available for the term "about" or "substantially" for each value. Where present, all ranges are inclusive and combinable. Additionally, references to values indicated in ranges include each value within that range.

[0028] When a list is presented, except where otherwise specified, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separate modality. For example, a list of modalities presented as "A, B or C" should be interpreted as including the modalities "A", "B", "C", "A or B", "A or C", "B or C" or "A, B or C".

[0029] It should be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, except where obviously incompatible or excluded, each individual modality is considered to be combinable with any other modality(s), and such combination is considered to be another modality. On the other hand, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. It is further noted that the claims may be worded to exclude any optional element. As such, this statement is intended to serve as a prior basis for use of such proprietary terminology as "exclusively", "only" and the like in connection with mention of claim elements, or use of a "negative" limitation. Finally, although an embodiment can be described as part of a series of steps, or part of a more general structure, each of said steps can also be considered as an independent embodiment in itself.

[0030] The term "subject", as used herein, refers to an animal being treated for a condition that requires Ibrutinib. In one embodiment, the subject is a human being. In another embodiment, the subject is an adult, including a youth, an adult or senior, or a child, including an adolescent.

[0031] The term "purified", as used herein, refers to Ibrutinib that contains less than about 1% impurities. In one embodiment, Ibrutinib contains less than about 0.5% impurities. In another embodiment, Ibrutinib contains less than about 0.1% impurities. In an additional embodiment, Ibrutinib is about 100% pure.

[0032] The terms intragranular and extragranular, as used herein, are known in the art of formulations. An intragranular form of a formulation component is added prior to granule formation. Similarly, an extragranular form of a component in the formulation is added to the granules of the formulation prior to compression. In simple terms, the extragranular portion breaks the composition into granules and the intragranular portion disintegrates the granules to release Ibrutinib, a salt, prodrug or metabolite thereof.

[0033] Abbreviations used in the present invention include CCS (croscarmellose sodium), CMC (microcrystalline cellulose), LSS (sodium lauryl sulfate), HPMC (hydroxypropyl methylcellulose; hypromellose), DSC (differential scanning calorimetry), BHT (hydroxy toluene butylated), BHA (butylated hydroxy anisole), sodium methyl parahydroxybenzoate, sodium ethyl, CLL (chronic lymphocytic leukemia) and SLL (small lymphocytic lymphoma).

A. Form of Ibrutinib

[0034] The compositions described herein contain Ibrutinib (Imbruvica) as the active agent. Ibrutinib is described and can be prepared as disclosed in US Patent Nos. 7,514,444; 8,003,309; 8,697,711; 8,735,403; 8,957,079 and 8,754,091, which are incorporated herein by reference. As known in the art, Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-1-piperidinyl]- 2-propen-1-one and has the following structure. Ibrutinib has a melting point range of about 149 °C to about 158 °C, a separation coefficient of about 4 at a pH of about 7, a dissociation constant of about 3.7, and a differential scanning calorimetry (DSC) melting point starting at about 156 °C.

[0035] The Ibrutinib used in the present invention may include other forms, including metabolites thereof, as long as the form of Ibrutinib is stable and non-toxic. The Ibrutinib form may also have some or the same activity as the Ibrutinib parent molecule. In one embodiment, an active metabolite of Ibrutinib has the following structure.

[0036] The form of Ibrutinib used in the present invention may encompass tautomeric forms of Ibrutinib, prodrugs and salts. In one embodiment, the Ibrutinib salts can be derived from pharmaceutically and physiologically acceptable acids, bases, alkali metals and alkaline earth metals. Physiologically acceptable acids include those of inorganic and organic acids. Inorganic acids are known in the art and include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acids. Organic acids are also known in the art and include, but are not limited to, lactic, formic, acetic, fumaric, citric, propionic, oxalic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, tartaric acids , malonic, malic, acetic phenyl, mandelic, embonic, methanesulfonic, ethanesulfonic, panthenoic, benzenesulfonic, toluenesulfonic, stearic, sulfanilic, alginic and galacturonic. Inorganic bases are known in the art and include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc sulfate or phosphates. Similarly, organic bases are known in the art and include, but are not limited to, N,N-dibenzyl ethylenediamine, chloroprocaine, choline, diethanol amine, ethylenediamine, meglumine and procaine. Alkali salts and alkaline earth metal salts can include, but are not limited to, sodium, potassium, calcium and magnesium salts in the form of esters and carbamates.

[0037] Ibrutinib prodrugs are also contemplated and include, but are not limited to, esters, carbamates, sulfates, ethers, oximes, carbonates, among others. Prodrug forms, which, when administered in such a form, are converted to the active moiety in vivo. See, Testa, "Prodrugs Revisited: The "Ad Hoc" Approach as a Complement to Ligand Design", Medicinal Research Reviews, 16(3): 233-241, ed., John Wiley & Sons (1996), which is incorporated in reference title.

[0038] A "metabolite" of Ibrutinib may also be used, as described herein. As known in the art, a metabolite is an Ibrutinib compound formed when the compound is metabolized as described in "The Pharmacological Basis of Therapeutics," 9th Edition, McGraw-Hill (1996), which is incorporated by reference.

B. Solid formulations

[0039] Ibrutinib can be formulated into solid formulations to be administered to an individual. The solid formulation is substantially dry, i.e. free of liquid. In one embodiment, the solid formulation is about 90% or more dry.

[0040] In one embodiment, a pharmaceutical composition discussed herein contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. As noted above, the Ibrutinib contained in such a composition may be the base molecule, salt, prodrug or metabolite thereof.

[0041] The composition contains from about 40 to about 45% by weight of Ibrutinib, a salt, prodrug or metabolite thereof. In one embodiment, the composition contains from about 41 to about 44% by weight of Ibrutinib, a salt, prodrug or metabolite thereof. In another embodiment, the composition contains from about 42 to about 43% by weight of Ibrutinib, a salt, prodrug or metabolite thereof. In another embodiment, the composition contains from about 42 to about 43% by weight of Ibrutinib, a salt, prodrug or metabolite thereof. In yet another embodiment, the composition contains from about 50 to about 140 mg of Ibrutinib, a salt, prodrug or metabolite thereof. In yet another embodiment, the composition contains about 50 mg of Ibrutinib, a salt, prodrug or metabolite thereof.

[0042] One or more suspending agents may be included in the liquid composition discussed herein. In one embodiment, microcrystalline cellulose is also included in the compositions described herein. In other embodiments, the composition contains from about 44 to about 47% by weight of microcrystalline cellulose. In another embodiment, the composition contains from about 45 to about 46% by weight of microcrystalline cellulose.

[0043] The compositions may also contain croscarmellose sodium. Croscarmellose sodium can be in an intragranular or extragranular form. In one embodiment, the compositions contain about 6% to about 8% by weight of croscarmellose sodium. In one embodiment, the composition contains about 7% by weight of croscarmellose sodium. In another embodiment, the composition contains from about 3 to about 5% by weight of intragranular croscarmellose sodium. In yet another embodiment, the composition contains about 4% by weight of intragranular croscarmellose sodium. In yet another embodiment, the composition contains from about 2 to about 4% by weight of extragranular croscarmellose sodium. In another embodiment, the composition contains about 3% by weight of croscarmellose sodium. In another embodiment, the composition contains about 13 mg intragranular croscarmellose sodium and about 9.9 mg intragranular extragranular croscarmellose sodium. In another embodiment, the composition contains about 4.6 mg of intragranular croscarmellose sodium and about 3.5 mg of extragranular croscarmellose sodium.

[0044] Sodium lauryl sulfate can also be included in the compositions discussed herein. Sodium lauryl sulfate can be in extragranular and/or intragranular form. In one embodiment, the composition contains from about 1 to about 5% by weight of sodium lauryl sulfate. In another embodiment, the composition contains from about 2 to about 4.5% by weight of sodium lauryl sulfate. In another embodiment, the composition contains from about 3 to about 4% by weight of sodium lauryl sulfate. In yet another embodiment, the composition contains from about 2.5 to about 3%, by weight, of intragranular sodium lauryl sulfate. In yet another embodiment, the composition contains about 3% by weight of intragranular sodium lauryl sulfate. In another embodiment, the composition contains from about 1 to about 2% by weight of extragranular sodium lauryl sulfate. In yet another embodiment, the composition contains about 1.4% by weight of extragranular sodium lauryl sulfate. In yet another embodiment, the composition contains about 9.4 mg of intragranular sodium lauryl sulfate and about 4.6 mg of extragranular sodium lauryl sulfate. In another embodiment, the composition contains about 3.3 mg of intragranular sodium lauryl sulfate and about 1.6 mg of extragranular sodium lauryl sulfate.

[0045] The compositions described herein may also contain magnesium stearate. Magnesium stearate can be in intragranular and/or extragranular form. In one embodiment, the composition contains from about 0.4 to about 0.6% by weight magnesium stearate. In another embodiment, the composition contains from about 0.4 to about 0.5% by weight magnesium stearate. In another embodiment, the composition contains from about 0.45 to about 0.5% by weight magnesium stearate. In another embodiment, the composition contains from about 0.2 to about 0.3% by weight of intragranular magnesium stearate. In yet another embodiment, the composition contains from about 0.2 to about 0.3% by weight of extragranular magnesium stearate. In yet another embodiment, the composition contains about 0.8 mg of intragranular magnesium stearate and about 0.8 mg of extragranular magnesium stearate. In another embodiment, the composition contains about 0.3 mg of intragranular magnesium stearate and about 0.3 mg of extragranular magnesium stearate.

[0046] In one embodiment, a pharmaceutical composition is described in the present invention and includes an intragranulation containing Ibrutinib, a salt, prodrug or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate.

[0047] In another embodiment, the pharmaceutical composition includes an extragranulation containing croscarmellose sodium, sodium lauryl sulfate and magnesium stearate.

[0048] In another embodiment, a pharmaceutical composition is provided that contains (i) about 40 to about 45% by weight of Ibrutinib; (ii) from about 44 to about 47% by weight of microcrystalline cellulose; (iii) from about 6 to about 8% by weight of croscarmellose sodium; (iv) from about 1 to about 5% by weight of sodium lauryl sulfate; and (v) from about 0.2 to about 0.3% by weight magnesium stearate.

[0049] In another further embodiment, a pharmaceutical composition is provided that contains (i) about 140 mg of Ibrutinib; (ii) about 151 mg of microcrystalline cellulose; (iii) about 23 mg of croscarmellose sodium; (iv) about 14 mg of sodium lauryl sulfate; and (v) about 1.6 mg of magnesium stearate.

[0050] In yet another embodiment, a pharmaceutical composition is provided that contains (i) about 50 mg of Ibrutinib; (ii) about 54 mg of microcrystalline cellulose; (iii) about 8 mg of croscarmellose sodium; (iv) about 5 mg of sodium lauryl sulfate; and (v) about 0.6 mg of magnesium stearate.

[0051] In another embodiment, pharmaceutical compositions containing the components of Table 1 are provided. Table 1

[0052] The solid compositions described herein contain particles of an ideal size to allow dissolution of the composition, for example, the particles are less than or equal to about 10 µ. The particle sizes of the composition can be measured by passing the solid composition through sieves of different sizes. If the particles of the composition are larger than the ideal size and if they have not been encapsulated in a capsule, or dissolved in one or more excipients, they can be subjected to additional milling and screening steps, among others, to reduce the particle size. Ibrutinib can optionally be micronised under nitrogen and conventional micronising techniques, for example with a jet mill or Trost, applied to non-micronised Ibrutinib. However, the compositions described herein are not limited to the method by which Ibrutinib is produced. Ibrutinib can have an average particle size of less than about 10 µm, less than about 7 µm, or less than about 5 µm. Specifically, 90% of the particles are smaller than or equal to about 10 µm and 50% are smaller than or equal to about 10 µm, as determined by the Malvern method, which is readily understood by one skilled in the art.

[0053] A variety of equipment can be used to carry out the manufacturing processes for preparing solid compositions and includes small, medium and large sized bags, different sized sieves and mixers. The process may also include mixing, extruding, melting, compacting and/or milling the composition, typically using compactors and mills selected by those skilled in the art. The milling step can be performed on particles of different sizes, i.e. large particles, powders and fine powders, to obtain a more uniform particle size. Milling can include one or more of the steps of separating, recycling, and screening to obtain the desired particle sizes. In one embodiment, the compositions can be prepared by dry blending Ibrutinib, based on the total weight of the composition, with the other components of the composition. In another embodiment, the compositions described herein are prepared by wet mixing Ibrutinib, based on the total weight of the composition, with the other components of the composition. Drying can be done using drying instruments selected by one skilled in the art. See, for example, Lachman, "The Theory and Practice of Industrial Pharmacy", 3rd ed. (1986), which is incorporated by reference.

[0054] In one embodiment, the solid compositions discussed herein are prepared as follows: (a) mixing microcrystalline cellulose, a first portion of sodium lauryl sulfate and a first portion of croscarmellose sodium; (b) mixing the product of step (a) with a first portion of Ibrutinib; (c) mixing the product of step (b) with a second portion of Ibrutinib; (d) mixing the product of step (c) with a first portion of magnesium stearate; (e) roller compacting the product of step (d); (f) milling the tapes produced in step (e); (g) mixing the granules produced in step (f) with a second portion of sodium lauryl sulfate and sodium croscarmellose; and (h) mixing the product of step (g) with a second portion of magnesium stearate. In another embodiment, solid compositions are prepared as described in Figure 1.

[0055] The solid compositions can then form a dosage unit suitable for administration to a patient, as determined by one skilled in the art. Suitable dosage units include oral dosage units. In one embodiment, the composition is added to a capsule. In another embodiment, the capsule is for pediatric administration. In yet another embodiment, the capsule is for administration by an adult who is unable to swallow a solid drug formulation. In another embodiment, the capsule is an HPMC (hypromellose) capsule. In yet another embodiment, the capsule is a gelatin capsule. In yet another embodiment, the capsule is a hard gelatine capsule. In yet another embodiment, the capsule is a conventional or dispersible capsule. In another embodiment, the capsule is a dark orange capsule. In another embodiment, the capsule is a size 0 capsule. In yet another embodiment, the dispersible capsule can be opened and the contents added to a substance, such as a food or drink, which can be ingested by the subject. The food can be a semi-solid or a solid, including soft food.

[0056] In another embodiment, capsules containing Ibrutinib are film-coated. Suitable film coatings are known to those skilled in the art. For example, the film coating can be a polymer such as HPMC, ethyl cellulose, polyvinyl alcohol or combinations thereof.

[0057] Solid compositions can also be added to a sachet. The term "sachet", as used herein, refers to a sachet or pouch that is capable of containing a composition described herein. The size of the sachet depends on the amount of the composition to be added. In one embodiment, the sachet is a single-dose sachet. In another embodiment, the sachet contains a batch amount of the compositions described herein. In the latter case, the patient, physician or caregiver measures the proper dosage of the compositions for administration. In another embodiment, the sachet is a paper/aluminium/polyethylene laminate or a polyester/aluminum/polyethylene laminate, both of which may optionally be located with a barrier coating such as ethylene vinyl acetate, polyvinyl acetate , polysiloxane or melamine, among others. In another embodiment, the sachet can be opened and the contents added to a substance, such as a food or drink, which can be ingested by the individual. The beverage may include, without limitation, water, milk or other common beverages.

[0058] The liquid formulation of solid composition (formulated in a liquid) can be administered to an individual through a feeding tube. The feeding tube can be temporarily or permanently attached to a patient using skill in the art. The patient can be conscious, semiconscious, or asleep, as needed, as determined by the attending physician. Various types of feeding tubes are known in the art and can be selected by the attending physician.

C. Liquid formulation

[0059] Ibrutinib can also be formulated into liquid formulations for administration to an individual. Liquids include, but are not limited to, suspensions, syrups and elixirs. Such dosage units are readily prepared using the methods described herein and those known to those skilled in the art. When formulated as a suspension, particle settling can occur, which requires resuspension of particles in the suspension using skill in the art.

[0060] The liquid compositions described herein contain Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide and water.

[0061] Accordingly, the liquid composition contains from about 30 to about 80 mg/ml of Ibrutinib, a salt, prodrug or metabolite thereof. In some embodiments, the composition contains from about 30 to about 50 mg/ml of Ibrutinib, a salt, prodrug or metabolite thereof. In other embodiments, the composition contains about 40 mg/ml of Ibrutinib, a salt, prodrug or metabolite thereof. In other embodiments, the composition contains from about 60 to about 80 mg/ml to about 70 mg/ml of Ibrutinib, a salt, prodrug or metabolite thereof. In still further embodiments, the composition contains about 70 mg/ml of Ibrutinib, a salt, prodrug or metabolite thereof.

[0062] One or more suspending agents may be included in the liquid composition discussed herein. In one embodiment, microcrystalline cellulose and sodium carboxymethylcellulose can also be included in the liquid composition. In some embodiments, the composition contains from about 12 to about 15 mg/ml of the suspending agent. In other embodiments, the composition contains from about 13 to about 15 mg/ml of the suspending agent. In other embodiments, the composition contains from about 12 to about 14 mg/ml of the suspending agent. In another embodiment, the composition contains about 13 mg/ml of the suspending agent. In another embodiment, the composition contains about 14 mg/ml of the suspending agent.

[0063] The composition may also contain one or more than one wetting agent. In one embodiment, the composition contains hydroxypropyl methylcellulose. In some embodiments, the composition contains from about 0.5 to about 3 mg/ml of the wetting agent. In other embodiments, the composition contains from about 2 to about 3 mg/ml of the wetting agent. In another embodiment, the composition contains about 2.5 mg/ml of the wetting agent. In other embodiments, the composition contains from about 0.5 to about 1.5 mg/ml of the wetting agent. In still other embodiments, the composition contains about 1 mg/ml of the wetting agent.

[0064] One or more buffering agents may be included in the solid or liquid composition. In one embodiment, the buffering agent is citric acid monohydrate or disodium hydrogen phosphate. In another embodiment, the composition contains from about 2.5 to about 3.5 mg/ml of the buffering agent. In some embodiments, the composition contains from about 1 to about 1.5 mg/ml of a first buffering agent. In other embodiments, the composition contains from about 0.5 to about 0.7 mg/ml of the buffering agent. In another embodiment, the composition contains about 1.5 mg/ml of a first buffering agent and about 1.5 mg/ml of a second buffering agent. In other embodiments, the composition contains about 1.6 mg/ml of a first buffering agent and about 1.4 mg/ml of a second buffering agent. In yet another embodiment, the composition contains about 1.5 mg/ml, or 1.6 mg/ml of citric acid monohydrate. In yet another embodiment, the composition contains about 1.4 mg/ml of disodium hydrogen phosphate.

[0065] Sweeteners may also be included in the solid or liquid compositions described herein. In one embodiment, the sweetener is sucralose. In another embodiment, the composition contains from about 0.1 to about 1.5 mg/ml of the sweetener. In other embodiments, the composition contains from about 0.5 to about 1.5 mg/ml of the sweetener. In another embodiment, the composition contains about 1 mg/ml of the sweetener. In another embodiment, the composition contains about 0.5 mg/ml of the sweetener.

[0066] One or more than one preservative may also be included in the solid or liquid compositions. The preservative desirably provides optimal microbiological activity in the liquid formulation. In one embodiment, the composition retains the optimal activity of the methyl/ethyl parabens. In one embodiment, the preservative is sodium methyl parahydroxybenzoate. In another embodiment, the preservative is sodium ethyl parahydroxybenzoate. In another embodiment, the composition contains from about 1.5 to about 2.5 mg/ml of the preservative. In other embodiments, the composition contains from about 1.5 to about 2 mg/ml of the preservative. In another embodiment, the composition contains from about 0.5 to about 1.8 mg/ml of a first preservative. In yet another embodiment, the composition contains from about 1.0 to about 1.8 mg/ml of a first preservative. In yet another embodiment, the composition contains from about 1.25 to about 1.5 mg/ml of a second preservative. In another embodiment, the composition contains about 1.1 mg/ml of a first preservative and about 0.6 mg/ml of a second preservative. In other embodiments, the composition contains about 1.4 mg/ml of a first preservative and about 0.7 mg/ml of a second preservative. In yet another embodiment, the composition contains about 1 mg/ml of sodium methyl parahydroxybenzoate. In yet another embodiment, the composition contains about 0.6 mg/ml of sodium ethyl parahydroxybenzoate. In further embodiments, the composition contains about 1.4 mg/ml of sodium methyl parahydroxybenzoate. In yet another embodiment, the composition contains about 0.7 mg/ml of sodium ethyl parahydroxybenzoate.

[0067] If the pH of the aqueous solution needs adjustment, a pH regulator can be included in the composition. A person skilled in the art should be able to select a suitable pH regulator to ensure a safe, stable and individual compatible composition. In one embodiment, the pH of the composition is adjusted to about 6. In another embodiment, the pH regulator is an acid or a base. In a further embodiment, the pH regulator is hydrochloric acid. In yet another embodiment, the pH regulator is concentrated hydrochloric acid. In yet another embodiment, the pH regulator is sodium hydroxide.

[0068] Finally, a sufficient amount of a diluent, such as water, can be included in the composition to ensure a volume of about 1 ml. In one embodiment, the diluent is purified water. Compositions containing smaller amounts of Ibrutinib can be prepared as described herein by diluting compositions containing larger amounts of Ibrutinib using the diluent.

[0069] In one embodiment, a pharmaceutical composition is provided that contains (i) about 70 mg/ml of Ibrutinib; (ii) about 13 mg/ml of microcrystalline cellulose and sodium carboxymethylcellulose; (iii) about 2.5 mg/ml of hydroxypropyl methylcellulose; (iv) about 1.5 mg/ml citric acid monohydrate; (v) about 1.4 mg/ml of disodium hydrogen phosphate; (vi) about 1 mg/ml of sucralose; (vii) about 1 mg/ml sodium methyl parahydroxybenzoate; and (viii) about 0.6 mg/ml sodium ethyl parahydroxybenzoate.

[0070] In another embodiment, a pharmaceutical composition is provided and contains the components of Table 2. Table 2

[0071] In other embodiments, a pharmaceutical composition is provided that contains (i) about 40 mg/ml of Ibrutinib; (ii) about 14 mg/ml of microcrystalline cellulose and sodium carboxymethylcellulose; (iii) about 1 mg/ml of hydroxypropyl methylcellulose; (iv) about 1.6 mg/ml citric acid monohydrate; (v) about 1.4 mg/ml disodium hydrogen phosphate; (vi) about 0.5 mg/ml sucralose; (vii) about 1.4 mg/ml sodium methyl parahydroxybenzoate; and (viii) about 0.7 mg/ml sodium ethyl parahydroxybenzoate.

[0072] In additional embodiments, a pharmaceutical composition is provided that contains the components of Table 3. Table 3

[0073] Liquid compositions can be prepared as follows: (a) mix water, microcrystalline cellulose, croscarmellose sodium; (b) mixing water with hydroxypropyl methylcellulose; (c) mixing the product of step (b) with Ibrutinib; (d) mixing the product of steps (a) and (c); (e) mixing the product of step (d) with sucralose; (f) mixing the product of step (e) with sodium methyl parahydroxybenzoate and sodium ethyl parahydroxybenzoate; (g) mixing the product of step (f) with the citric acid monohydrate; and (h) mixing the product of step (g) with anhydrous disodium hydrogen phosphate. The process may further include (i) adjusting the pH of the product of step (h) to a pH of about 6. In one embodiment, step (i) is carried out using hydrochloric acid or sodium hydroxide. The process may also include adding water to the product of step (h) or (i). It is also envisaged that the product of step (a) can be homogenized using known techniques.

[0074] The liquid formulations can then be stored as a batch unit or dispensed into separate smaller vials for storage or customer purchase. The person skilled in the art would readily be able to select suitable vials for use in the present invention. In one embodiment, the liquid composition is added to a vial. In another embodiment, the bottle is glass. In another embodiment, the vial is clear or amber. In another embodiment, the vial can be sealed. In yet another embodiment, the vial is sealed with a rubber stopper. In another embodiment, the vial is sealed with a Teflon coated rubber stopper. The cap optionally contains a removable, i.e., tear-off, aluminum cap. In yet another embodiment, the vial is a 10ml/20mm vial. In yet another embodiment, the flask is a drinking flask.

[0075] Additionally, the pharmaceutical will be administered as a single dose to each subject after adequate shaking of the sample to resuspend the particles prior to administration. Furthermore, after administration of the pharmaceutical product, the vial will be rinsed with an adequate amount of water and the entire contents of the vial will be administered to the patient. For the reasons mentioned above, even if decantation occurs, it is not expected to have an effect on the administered dose.

D. Additional Components

[0076] Other components may be added to the compositions described herein, as determined by one skilled in the art. The additional components can be inert and do not interfere with the function of the necessary components of the compositions. The compositions may therefore include other adjuvants, syrups, elixirs, diluents, binders, lubricants, surfactants, granulating agents, disintegrating agents, emollients, metal chelating agents, pH adjusters, color preservatives, antioxidants, agents, surfactants , fillers, disintegrants or combinations thereof.

[0077] Preservatives may include ascorbic acid, BHT and BHA, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate or combinations thereof.

[0078] Sweeteners, such as natural or artificial sweeteners, or a combination thereof, may be included in the compositions described herein. In one embodiment, the natural sweetener is sucrose, including raw sugar, granulated sugar, brown sugar, icing sugar and turbinado sugar, fructose, honey, fruit sugar, high fructose corn syrup, corn syrup, sugar alcohols, such as mannitol, sorbitol, xylitol, erythritol, hydrogenated starch hydrolyzate, lactitol or maltitol, isomaltitol, dextrose, invert sugar, agave nectar, glucose, lactose, maltose, maple sugar, apricot sugar, molasses , stevia extract, tagatose, trehalose, or any combination thereof. In another embodiment, the artificial sweetener is sucralose, aspartame, saccharin, neotame, advantame or acesulfame potassium. In yet another embodiment, sugar can be included in the compositions.

[0079] Binders may include, but are not limited to, cellulose, methylcellulose, hydroxy methyl cellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, non-crystalline cellulose, polypropyl pyrrilidone, polyvinyl pyrrolidone ( povidone, PVP), gelatin, gum arabic and acacia, polyethylene glycols, starch, sugars such as sucrose, kaolin, dextrose and lactose, cholesterol, tragacanth, stearic acid, gelatin, casein, lecithin (phosphatides), cetostearyl alcohol, cetyl alcohol, cetyl esters wax, dextrates, dextrin, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyoxyethylene alkyl ethers, castor oil polyoxyethylene derivatives, polyoxyethylene stearates, polyvinyl alcohol and gelatin, among others.

[0080] Lubricants may include anhydrous silicic acid, talc, stearic acid, sodium lauryl sulfate, magnesium stearate, and sodium stearyl fumarate, among others.

[0081] Granulating agents may include, but are not limited to, silicon dioxide, starch, calcium carbonate, pectin, crospovidone, and polyplasdone.

[0082] Disintegrating agents or disintegrators may include, but are not limited to, starch, carboxymethylcellulose, substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, calcium citrate, sodium starch glycolate, starch pre- gelatinized or crospovidone.

[0083] Emollients may include, but are not limited to, stearyl alcohol, mink oil, cetyl alcohol, oleyl alcohol, isopropyl laurate, polyethylene glycol, olive oil, petroleum gel, palmitic acid, oleic acid, and myristate of myristille.

[0084] Surfactants may include, but are not limited to, polysorbates, sorbitan esters, poloxamer or sodium lauryl sulfate.

[0085] Metal chelating agents may include, but are not limited to, physiologically acceptable chelating agents, including edetic acid, malic acid, or fumaric acid.

[0086] The compositions described herein, in dry or liquid form, have a pH of about 5.5 to about 6.5. pH adjusters can be used to adjust the pH of a solution containing Ibrutinib to about 6. pH adjusters can include, but are not limited to, citric acid, ascorbic acid, fumaric acid, malic acid, hydrochloric acid, sodium hydroxide, the salts thereof, or combinations thereof.

E. Stability of compositions

[0087] The Ibrutinib compositions as described herein, whether in solid or liquid form, are stable under neutral conditions, i.e. a pH of about 6 to about 8. The compositions are also stable under light irradiation. In one embodiment, the compositions are stable over a period of about 1 month for samples stored at different temperatures and humidities. The term stable, as used herein, refers to compositions described herein that degrade less than about 3%. In one embodiment, the compositions are stable from about 20°C/50% relative humidity to about 45°C/75% relative humidity. In another embodiment, the compositions described herein degrade less than about 3% over a period of time greater than 1 month at temperatures of about 25°C or greater and at a relative humidity equal to or greater than that about 60%.

[0088] Solid compositions are also stable for at least about 6 hours when combined with an agent that is semi-solid or liquid. In one embodiment, the solid compositions can be suspended in a liquid or semi-solid and redispersed after 6 hours. In another embodiment, solid compositions suspended in a liquid or semi-solid are stable for up to about 6 hours.

[0089] Stability can be monitored by various methods known in the art. In one embodiment, the capsules and liquid can be observed to detect any change in physical appearance or color. In one embodiment, a change in capsule color or deformation in the capsule may indicate degradation or deterioration of the capsule and thus affect its safety or efficacy.

[0090] The compositions described herein can be stored at reduced, ambient or selected temperatures. In one embodiment, the compositions are stored at temperatures from about 0 to about 10°C. In another embodiment, the compositions are stored at temperatures from about 2 to about 8°C. Compositions can be stored in the absence of water, air and moisture. However, storage at room temperature, among other atmospheric conditions, does not affect the overall stability of the compositions.

F. Methods of using compositions

[0091] Also provided are methods of administering Ibrutinib to a patient, wherein the method includes administering a composition described herein to a patient. The compositions are therefore useful in treating or preventing disease. In some embodiments, the diseases are those mentioned in US Patent Nos. 8,497,277; 8,476,284; 8,703,780 and 8,754,090, which are incorporated herein by reference.

[0092] The compositions are useful in the therapeutic treatment of a subject having one or more of any of the diseases mentioned herein. The compositions can also be useful prophylactically, that is, the compositions can be administered to a patient susceptible to, or otherwise at risk of, developing a malignancy. The compositions can further be used in maintenance therapy, i.e. administered to a patient who is in remission.

[0093] In certain embodiments, the methods of the present invention include treating one or more autoimmune diseases. In one embodiment, the autoimmune disorder is inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wgener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis , neuromyotonia, scleroderma or vulvodynia.

[0094] In another embodiment, the methods include treating one or more heteroimmune disorders. In one embodiment, the heteroimmune disorder is graft-versus-host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.

[0095] In certain embodiments, the methods of the present invention include treating one or more inflammatory diseases. In one embodiment, the inflammatory disease is arthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis , pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis or vulvitis.

[0096] In still other embodiments, the methods include treating one or more types of cancer. In one embodiment, the cancer is a B-cell proliferative disorder. In yet another embodiment, the cancer is a hematologic malignancy. In another embodiment, the cancer is B-cell prolymphocytic leukemia, leukemia, lymphoma, lymphoproliferative disease, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, myeloid disorder, plasma cell myeloma, plasmacytoma, large B-cell lymphoma of the mediastinum, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, non-Hodgkin CLL, LLP, high-risk CLL, non-CLL/LLL lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, small cell lymphoma lymphoma, multiple myeloma, marginal zone lymphoma, non-Burkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, acute or chronic myeloid leukemia, myelodysplastic syndrome, lymphoblastic leukemia, relapsed or refractory large B-cell lymphoma , relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, relapsed or refractory CLL, relapsed or refractory PLL, relapsed or refractory multiple myeloma, Burkitt's lymphoma, cutaneous B-cell lymphoma, cutaneous marginal zone lymphoma, diffuse lymphoma mixed small and large cell, diffuse small cleaved cell, extranodal follicular small cleaved cell, follicular large and small cleaved cell mixed, follicular large cell, intravascular lymphomatosis, immunoblastic large cell lymphoma, large cell lymphoma, lymphoid tissue-associated lymphoma mucosa, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, hairy cell leukemia. In another embodiment, the B-cell proliferative disorder is non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, plasma cell myeloma, or chronic lymphocytic leukemia. In another embodiment, the B-cell proliferative disorder is diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and Burkitt's lymphoma. In yet another embodiment, the cancer is leukemia. In yet another embodiment, the cancer is a lymphoma.

[0097] In still other embodiments, the methods include treating a thromboembolic disorder. In one embodiment, the thromboembolic disorder is myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass surgery, restenosis after aortocoronary bypass surgery, stroke, transient ischemia, a peripheral arterial occlusive disorder, pulmonary embolism or deep vein thrombosis.

[0098] Ibrutinib dosage requirements may vary based on the severity of symptoms presented and the specific individual being treated. Treatment can be started with small dosages less than the optimal dose of Ibrutinib. Thereafter, the dosage may be increased until the optimum effect under the circumstances is reached. Precise dosages will be determined by the physician based on experience with the individual being treated. In one embodiment, the composition is administered at a concentration that will provide effective results without causing any harmful or unacceptable harmful side effects.

[0099] The term "effective amount" as used herein refers to a sufficient amount of an agent or compound being administered that alleviates one or more symptoms of a B cell proliferative disorder. /or the alleviation of the signs, symptoms or causes of the disorder. In certain embodiments, the effective amount achieves the desired pharmacological effect or therapeutic improvement without undue adverse side effects.

[0100] An effective amount of Ibrutinib may vary depending on the components of the composition, the mode of administration, the severity of the condition being treated, the age and weight of the patient and any other active ingredients used in the composition. The dosage regimen can also be adjusted to provide the optimal therapeutic response. Several divided doses can be administered daily, for example in divided doses 2 to 4 times a day, or a single dose can be given. The dose may, however, be proportionately reduced or increased, as indicated by the demands of the therapeutic situation. In one embodiment, administration is daily, weekly, or monthly. In another embodiment, administration is daily. The composition can be administered daily. In some embodiments, the composition can be administered every other day. In some embodiments, the composition can be administered one or more times per day. In some embodiments, the composition can be administered two or more times per day. In some embodiments, the composition can be administered three or more times per day.

[0101] Dosages can also be reduced or increased based on periodic administration. The attending physician also has the flexibility to continue the same administration over a period of time or may decide to change the administration schedule. This may be the result of improved, adverse but not fatal conditions, reactions to the composition or the like. If the administration is interrupted, a new administration can be continued if the patient's condition stabilizes or improves. Consequently, the dose, frequency of administration, or a combination thereof, can be reduced or increased as needed.

[0102] The administered amount of Ibrutinib may vary depending on the severity of the disease, the individual's weight, the individual's age, among others. In one embodiment, an effective amount is from about 0.1 to about 5000 mg/day. In one embodiment, an effective amount of Ibrutinib is from about 1 to about 1500 mg/day. In another embodiment, the effective amount of Ibrutinib is from about 20 to about 450 mg/day. In another embodiment, the effective amount of Ibrutinib is from about 20 to about 420 mg/day. In yet another embodiment, the effective amount of Ibrutinib is from about 30 to about 300 mg/day. In yet another embodiment, the effective amount of Ibrutinib is from about 50 to about 200 mg/day. In another embodiment, the effective amount of Ibrutinib is from about 70 to about 140 mg/day.

[0103] The desired dose may conveniently be presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at suitable intervals, for example as two, three, four or more sub-doses per day .

[0104] The compositions may be administered to an individual by any suitable route, as directed by the attending physician. In one embodiment, the compositions are administered orally.

[0105] The compositions can be co-administered with one or more than a second agent. The second agent can be administered prior to, concurrently with, or subsequent to the compositions discussed herein. In some embodiments, the second agent comprises a chemotherapeutic agent, steroid, immunotherapeutic agent, among others. In another embodiment, the second agent is one or more of actinomycins, alkylating agents, alitretinoin, altretamine, ansacrine, anagrelide, angiogenesis inhibitors, antibodies, antiandrogens, antiestrogens, antimetabolites, anthracyclines, arsenic trioxide, asparaginase, inhibitor B cell receptor pathway (CD79A inhibitor, CD79B inhibitor, CD19 inhibitor, Lyn inhibitor, Syk inhibitor, PI3K inhibitor, Blnk inhibitor, PLCy inhibitor, PKCP inhibitor), basiliximab, bexarotene, bortezomib, calcineurin inhibitors, canakinumab, celecoxib, ceradenovec, colchicine derivatives, cytotoxic antibiotics, daclizumab, denileucine diftitox, DNA damaging agent, epoxides, estramustine, estrogens, ethylene imines, folic acid analogues, gonad-releasing interferons - tropine, growth factors, HDAC inhibitor, hedgehog inhibitor, Hsp90 inhibitor, histone deacetylase inhibitor, hormones, hormone analogues, hormone antagonists, hydroxycarbamide, IAP inhibitor, ibritumomab immunostimulants, immunosuppressants, interleukin, interleukins, irinotecan, Jakl/2 inhibitor, lonidamine, masoprocol, mepolizumab, miltefosine, mitoguazone, mitotane, monoclonal antibodies, mTOR inhibitor, methyl hydrazine, nitrogen mustards, nitrosoureas, PI3K inhibitor, oblimerase no, PARP inhibitor, pegaspargase, pentostatin, PKC inhibitor, plant alkaloids, platinum compounds (carboplatin, cisplatin, oxaliplatin or satraplatin), podophyllotoxin derivatives, progestins, proteasome inhibitors, protein kinase inhibitors, protease, purine analogues, pyrimidine analogues, radioimmunotherapeutics, sensitizers, romidepsin, thiazofurin, sitimagen, topotecan, tretinoin, tumor necrosis factors, TNF-a inhibitors, tocilizumab, telomerase inhibitor, tiuxethane, tositumomab, triazenes, ustekinumab, vinca alkaloids or vorinostat. In another embodiment, the second agent includes, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldesleucine; alentuzumab, altretamine; ambomycin; amethantrone acetate; aminoglutethimide; ansacrine; anastrozole; anthramycin; asparaginase; asperline; azacitidine; azatepa; azotomycin; batimastate; bendamustine, bevacizumab; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesine; bleomycin sulfate; brequinar sodium; bropyrimine; busulfan; cactinomycin; calusterone; characemid; carbethimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; cetuximab; chlorambucil; cyrolemycin; cladribine; crisnatol mesylate; crizotinib; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; empromate; epipropidin; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; ethanidazole; etoposide; etoposide phosphate; etorphine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; 5-fluorouracil; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; gentuzamab; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II, interferon a-2a; interferon a-2b; interferon a-nl; interferon a-n3; interferon ß-1 a; interferon y-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaryl; mercaptopurine; methotrexate; sodium methotrexate; methoprine; meturedepa; mitindomide; mitocarcin; mitochromin; mitogilin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; Nexavar®; nocodazole; no-galamycin; ofatumumab; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobromane; piposulfan; pyroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurine; riboprin; rituximab; roglethimide; safingol; safingol hydrochloride; semustine; sintrazen; sodium sparphosate; sparmycin; spirogermanium hydrochloride; spiromustine; spiroplatin; Sprycel®; streptonigrin; streptozocin; sulofenur; Sutent®; talisomycin; Tarceva®; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; temozolomide; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; thiazofurine; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; Tykerb®; uracil mustard; uredepa; va-preotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; wortmannin; zeniplatin; zinostatin; zorubicin hydrochloride.

G. Kits containing the compositions

[0106] Also provided are kits or packs containing Ibrutinib and an optional suitable vehicle for administration to a mammalian patient, as discussed above. In one embodiment, the capsules can be packaged in vials, blister packs, pill boxes, or the like. In another embodiment, the liquid formulation can be packaged in a vial optionally lined with a pierceable cap, ampoule, dropper, or in a pouch of saline.

[0107] The kits or packages containing the compositions described herein are designed for use in the methods described herein. The kit can optionally further contain instructions for administering the composition, a suitable vehicle for administering the composition, one or more instruments including, but not limited to, a syringe, pipette, forceps, measuring spoon or the like. Other components for inclusion in kits would be obvious to those skilled in the art, given the desired indication and mode of administration.

[0108] The following examples are provided to illustrate some of the concepts described in this disclosure. While each example is intended to provide specific individual embodiments of composition, methods of preparation and use, none of the examples should be considered to limit the more general embodiments described herein.

[0109] In the examples below, efforts have been made to ensure accuracy with respect to the numbers used (eg, amounts, temperature, etc.), but some experimental error and bias must be taken into account. Except where otherwise noted, temperature is in degrees Celsius, pressure is at or close to atmospheric pressure.

Examples Example 1: Solid compositions containing Ibrutinib

[0110] Solid compositions containing Ibrutinib were prepared for inclusion in a capsule, as described below.

A. 140 mg capsule

[0111] In this process, an intragranular blend was prepared by mixing CMC (151.49 mg; Avicel PH 101), SLS (9.40 mg; Kolliphor; fine) and CCS (13.10 mg; Ac-di -sun) in a container. This was then mixed with Ibrutinib (70 mg; micronised, Lonza, Nansha). The remaining Ibrutinib (70 mg) was then added and the composition mixed. Magnesium stearate (0.8 mg; non-bovine #5712) was then added to this mixture which was blended to provide a roll pre-compaction blend. The pre-roller compaction blend was then roller compacted to form ribbons. The tapes were then milled to provide a granule-containing composition.

[0112] The granules were then mixed with a second portion of SLS (4.6 mg; Kolliphor; fine) and CCS (9.9 mg; Ac-di-sol). To this blend was then added a second portion of magnesium stearate (0.8 mg; non-bovine #5712) to provide a lubricated blend. This lubricated blend was then added to a size 0 dark orange hard gelatin capsule.

B. Ibrutinib 50 mg capsule

[0113] In this process, an intragranular blend was prepared by mixing CMC (54.07 mg; Avicel PH 101), SLS (3.36 mg; Kolliphor; fine), and CCS (4.68 mg; Ac- di-sun). This was then mixed with Ibrutinib (25 mg; micronised, Lonza, Nansha). The remaining Ibrutinib (25 mg) was then added and the composition mixed. Magnesium stearate (0.29 mg; non-bovine #5712) was then added to this mixture which was blended to provide a roller pre-compaction blend. The pre-roller compaction blend was then roller compacted to form ribbons. The tapes were then milled to provide a granule-containing composition.

[0114] The granules were then mixed with a second portion of SLS (1.64 mg; Kolliphor; fine) and CCS (3.54 mg; Ac-di-sol). To this blend was then added magnesium stearate (0.29 mg; non-bovine #5712) to provide a lubricated blend. This oiled blend (117.87 mg) was then added independently to a dark orange size 0 hard gelatin capsule and a dark orange dispersible capsule.

Example 2: Liquid Suspension Composition Containing Ibrutinib (i) 70 mg/ml Ibrutinib Liquid Suspension

[0115] A liquid composition containing 70 mg/ml of Ibrutinib was prepared. Specifically, water (300 ml) was mixed with a CCS CMC composition (Avicel RC591; 6.5 g) for 30 minutes. This dispersion was then homogenized for 30 seconds using an L2R SILVERSON® homogenizer at maximum speed (7500 rpm). HPMC (2910 5 mPAS; 1.25 g) was mixed with water (120 ml) until smooth using a magnetic stirrer. Micronized Ibrutinib (35 g, Lonza Clinical) was then added to the HPMC solution and mixed for 120 minutes. The CMC/CCS dispersion was then mixed with the Ibrutinib mixture. Sucralose (0.5 g), sodium methyl parahydroxybenzoate (0.5725 g) and sodium ethyl parahydroxybenzoate (0.2875 g) were added to the mixture. After about 10 minutes of stirring, citric acid monohydrate (0.7565 g) and parenteral anhydrous disodium hydrogen phosphate (0.69 g) were then added to this mixture. The mixture was stirred for about 10 minutes until the contents were solubilized. The pH of the mixture was measured and found to be 5.99, thus eliminating the need to adjust the pH. The mixture was then diluted with purified water to a final weight of 510.5 g. The pH of the mixture was again measured and found to be around 6.

[0116] The concentration of each component in the final liquid composition is provided in Table 2. (ii) 40 mg/ml liquid suspension of Ibrutinib

[0117] A liquid composition containing 40 mg/ml of Ibrutinib was prepared. Specifically, water (300 ml) was mixed with a CCS CMC composition (Avicel RC591; 7 g) for 30 minutes. This dispersion was then homogenized for 30 seconds using an L2R SILVERSON® homogenizer at maximum speed (7500 rpm). HPMC (2910 5 mPas; 0.5 g) was mixed with water (120 ml) until smooth using a magnetic stirrer. Micronized Ibrutinib (20 g, Lonza Clinical) was then added to the HPMC solution and mixed for 120 minutes. The CMC/CCS dispersion was then mixed with the Ibrutinib mixture. Sucralose (0.25 g), sodium methyl parahydroxybenzoate (0.6791 g) and sodium parahydroxybenzoate (0.3387 g) were added to the mixture. After about 10 minutes of stirring, citric acid monohydrate (0.801 g) and parenteral anhydrous disodium hydrogen phosphate (0.69 g) were then added to this mixture. The mixture was stirred for about 10 minutes until the layers dissolved. The pH of the mixture was measured and found to be around 5.99, thus eliminating the need to adjust the pH. The mixture was then diluted with purified water to a final weight of 507g. This mixture was then homogenized. The pH was again measured and found to be around 6.

[0118] The concentration of each component in the final liquid composition is provided in Table 3.

Example 3: Large scale preparation of a suspension containing Ibrutinib 4 L batch preparation

[0119] Purified water (480 g) was added to a vessel and heated to about 83 °C at a stirring speed of 400 rpm for about 60 minutes. HPMC (10.002 g) was slowly added to the vessel and the mixture was stirred at a speed of about 7600 for about 4 minutes until the mixture was homogenized. To this vessel was added purified water (480 g) and then the mixture was stirred for about 5 minutes at a speed of about 500 rpm at room temperature until the mixture was solubilized. Ibrutinib (278.6 g) was added to the mixture, which was stirred at 600 rpm for about 2 h until homogeneous. The mixture was monitored through a microscope to observe the presence of agglomerates.

[0120] Purified water (2400 g) was then added to a second container. At a speed of about 500 rpm, CMC (51.74 g; Avicel) was added to the second vessel over a period of 3 minutes, followed by stirring at a speed of about 400 rpm for about 60 minutes. This mixture was then homogenized using an agitation speed of about 7600 tr/min for a period of about 4 minutes. The mixture was monitored through a microscope to observe the presence of agglomerates.

[0121] The mixture from the first vessel was then added to the mixture from the second vessel, and the combined contents were agitated for about 5 hours at a speed of about 500 rpm. The first container was rinsed with purified water (200 ml) and added to the second container. Under moderate agitation conditions, sucralose (40038 g), sodium methyl parahydroxybenzoate (45838 g) and sodium ethyl parahydroxybenzoate (2300 g) were sequentially added to the second vessel and the mixture was stirred for about 11 minutes. , until the solids dissolved. Citric acid monohydrate (6052 g) was then added to the second beaker and the mixture stirred for about 10 minutes. Anhydrous disodium hydrogen phosphate (5521 g) was then added and the mixture stirred for about 10 minutes until the contents solubilized. The pH of the solution was measured and found to be around 5.94, thus eliminating the need to adjust the pH.

[0122] The mixture was then diluted with purified water (4064 g) to a final weight of 4084 g. This mixture was then homogenized. The pH was again measured and found to be about 5.98. Aliquots (8 ml) of the mixture were then withdrawn under constant stirring at a speed of from about 500 to about 1300 rpm over a period of about 75 minutes. Each aliquot was added to an amber glass vial (10 ml), a Flurotec-coated rubber injection plug (20 mm), then inserted into the vial, and the plug was affixed to an aluminum cap with a tear-off lid. (20 mm). See Figure 3.

Example 4: Stability studies of Ibrutinib formulations

[0123] The stability of the solid composition described here was evaluated in 3 liquids. Specifically, the contents of 4 dispersible capsules described herein (each containing 140 mg of solid composition) were dissolved in water (100 ml), milk (100 ml) and orange juice (100 ml) at room temperature. After about 6 hours, the colors of the milk and orange juice solutions remained unchanged, while the aqueous solution became milky white.

[0124] All three Ibrutinib formulations were found to be stable using liquid chromatography. Specifically, most of the Ibrutinib active agent with minor amounts of impurities was recovered from these formulations after resting for 6 hours.

Example 5: Feeding tube studies using Ibrutinib formulations

[0125] Feasibility studies were conducted on feeding tubes using a composition described herein. Specifically, two formulations were prepared, each containing water (20 ml) and the contents of 4 dispersion capsules described herein (total of 560 mg active equivalent granules). By passing the formulations through 2.2 mm and 2.7 mm ID feed tubes, it was observed that the formulations (containing the water and composition) passed through the tubes under gravity and without obstruction.

[0126] It was also discovered that the tubes could be reused before introducing another formulation. Specifically, air was blown through the tubes by applying a small amount of pressure using a syringe. Additional formulations could then be passed through the tubes without any interruption. It should be understood that, although the invention has been described in conjunction with specific preferred embodiments thereof, the aforementioned description and examples which follow are intended to illustrate and not to limit the scope of the invention. Those skilled in the art will understand that various changes can be made and equivalents can be substituted without departing from the scope of the invention, and additionally that other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention belongs. In addition to the embodiments described herein, the present invention contemplates and claims those inventions that result from the combination of features of the invention cited herein and those of the cited prior art references that complement the features of the present invention. Similarly, it will be appreciated that any material, feature or article described can be used in combination with any other material, feature or article, and such combinations are considered within the scope of this invention.

[0127] The descriptions of each patent, patent application, and publication cited or described herein are hereby incorporated by reference in their entirety for multiple purposes.

Claims (32)

1. Pharmaceutical composition, characterized in that it comprises Ibrutinib, or a salt thereof, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, ethyl parahydroxybenzoate, - sodium hydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide and water. 2. Pharmaceutical composition according to claim 1, characterized in that it comprises 30 to 80 mg/mL of Ibrutinib. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that it comprises 30 to 50 mg/mL of Ibrutinib. 4. Pharmaceutical composition according to claim 1, characterized in that it comprises 60 to 80 mg/mL of Ibrutinib. 5. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that it comprises 12 to 15 mg/mL of microcrystalline cellulose and sodium carboxymethylcellulose. 6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it comprises 13 to 15 mg/mL of microcrystalline cellulose and sodium carboxymethylcellulose. 7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that it comprises 12 to 14 mg/mL of microcrystalline cellulose and sodium carboxymethylcellulose. 8. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that it comprises 0.5 to 3 mg/mL of hydroxypropylmethylcellulose. 9. Pharmaceutical composition according to any one of claims 1 to 8, characterized in that it comprises 2 to 3 mg/mL of hydroxypropylmethylcellulose. 10. Pharmaceutical composition according to any one of claims 1 to 9, characterized in that it comprises 0.5 to 1.5 mg/mL of hydroxypropylmethylcellulose. 11. Pharmaceutical composition according to any one of claims 1 to 10, characterized in that it comprises 1.4 to 1.7 mg/mL of citric acid monohydrate. 12. Pharmaceutical composition according to any one of claims 1 to 11, characterized in that it comprises about 1.4 mg/mL of disodium hydrogen phosphate. 13. Pharmaceutical composition according to any one of claims 1 to 12, characterized in that it comprises 0.5 to 1.5 mg/mL of sucralose. 14. Pharmaceutical composition according to any one of claims 1 to 13, characterized in that it comprises 1 to 1.5 mg/mL of sodium methyl parahydroxybenzoate. 15. Pharmaceutical composition according to any one of claims 1 to 14, characterized in that it comprises 0.5 to 0.7 mg/mL of sodium ethyl parahydroxybenzoate. 16. Pharmaceutical composition according to any one of claims 1 to 15, characterized in that it comprises a sufficient amount of concentrated hydrochloric acid to maintain a pH of around 6. 17. Pharmaceutical composition according to any one of claims 1 to 16, characterized in that it comprises a sufficient amount of sodium hydroxide to maintain a pH of around 6. 18. Pharmaceutical composition according to any one of claims 1 to 17, characterized in that it comprises a sufficient amount of water to guarantee a total volume of 1 mL. 19. Pharmaceutical composition according to any one of claims 1 to 18, characterized in that it is a suspension liquid. 20. Pharmaceutical composition according to claim 1, characterized in that it comprises: (i) about 70 mg/ml of Ibrutinib; (ii) about 13 mg/ml of microcrystalline cellulose and sodium carboxymethylcellulose; (iii) about 2.5 mg/ml of hydroxypropyl methylcellulose; (iv) about 1.5 mg/ml citric acid monohydrate; (v) about 1.4 mg/ml of disodium hydrogen phosphate; (vi) about 1 mg/ml of sucralose; (vii) about 1 mg/ml of sodium methyl parahydroxybenzoate; and (viii) about 0.6 mg/ml sodium ethyl parahydroxybenzoate. 21. Pharmaceutical composition according to claim 1, characterized in that it comprises: (i) about 40 mg/ml of Ibrutinib; (ii) about 14 mg/ml of microcrystalline cellulose and sodium carboxymethylcellulose; (iii) about 1 mg/ml of hydroxypropyl methylcellulose; (iv) about 1.6 mg/ml citric acid monohydrate; (v) about 1.4 mg/ml of disodium hydrogen phosphate; (vi) about 0.5 mg/ml sucralose; (vii) about 1.4 mg/ml sodium methyl parahydroxybenzoate; and (viii) about 0.7 mg/ml sodium ethyl parahydroxybenzoate. 22. Use of a composition as defined in any one of claims 1 to 21, characterized in that it is for the preparation of a drug for the treatment of a proliferative disease of B cells. 23. Use according to claim 22, characterized by the fact that said B-cell proliferative disease is a non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, plasma cell myeloma or chronic lymphocytic leukemia. 24. Use according to claim 23, characterized in that the non-Hodgkin's lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma and Burkitt's lymphoma. 25. Use according to any one of claims 22 to 24, characterized in that the composition is administered orally. 26. Use of a composition as defined in any one of claims 1 to 21, characterized in that it is for preparing a drug for the treatment of lymphoma. 27. Use of a composition as defined in any one of claims 1 to 21, characterized in that it is for the preparation of a drug for the treatment of leukemia. 28. Use of a composition as defined in any one of claims 1 to 21, characterized in that it is for preparing a drug for the treatment of mantle cell lymphoma. 29. Use according to any one of claims 22 to 28, characterized by the fact that the individual is a human being. 30. Use according to any one of claims 22 to 29, characterized in that the composition is spread on food. 31. Use according to claim 30, characterized in that the food is a soft food. 32. Process for preparing a composition, as defined in claim 1, characterized in that it comprises: (a) mixing water, microcrystalline cellulose, sodium croscarmellose; (b) mixing water with hydroxypropyl methylcellulose; (c) mixing the product of step (b) with Ibrutinib; (d) mixing the product of steps (a) and (c); (e) mixing the product of step (d) with sucralose; (f) mixing the product of step (e) with sodium methyl parahydroxybenzoate and sodium ethyl parahydroxybenzoate; (g) mixing the product of step (f) with citric acid monohydrate; and (h) mixing the product of step (g) with anhydrous disodium hydrogen phosphate.