Formulation / Composition Containing Ibrutinib

Abstract

Ibrutinib: [Formula 1] Formulations / compositions comprising (I) as well as processes for preparing such formulations / compositions and methods for treating diseases or conditions comprising the use of such formulations / compositions are disclosed.

Description

Technical Field

[0001] The present invention relates to Bruton's tyrosine kinase (BTK) inhibitors, particularly formulations of ibrutinib. The present invention also relates to processes for preparing such formulations / compositions comprising ibrutinib and methods of using such formulations / compositions in the treatment of hematological malignancies.

Background Art

[0002] Ibrutinib is an organic small molecule having the IUPAC name 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one. It is described in many published documents including WO 2008 / 039218 pamphlet (Example 1b) of international patent application and is described as an irreversible inhibitor of Btk.

[0003] Ibrutinib plays a role in targeting B cell malignancies. Ibrutinib blocks signals that stimulate malignant B cells to grow and divide uncontrollably. Therefore, clinical trials are being conducted for various hematological malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, Waldenström macroglobulinemia and multiple myeloma. Also, in some countries, it has received regulatory approval for specific diseases. For example, it was approved by the US FDA for the treatment of mantle cell lymphoma in November 2013, for the treatment of chronic lymphocytic leukemia in February 2014, and for the treatment of Waldenström macroglobulinemia in January 2015. It is marketed under the trade name Imbruvica (registered trademark).

[0004] The crystalline forms of ibrutinib are disclosed in WO 2013 / 184572. Formulations of ibrutinib are described in documents such as WO 2014 / 004707, WO 2014 / 0336203, WO 2016 / 022942, WO 2016 / 141068, WO 2016 / 164404, WO 2017 / 125423 and WO 2017 / 125424. Co-crystals of ibrutinib are also disclosed in WO 2016 / 160604 and WO 2016 / 156127.

[0005] Alternative formulations of ibrutinib are needed and / or desired, particularly in the pediatric population. In the case of pediatric formulations, there are many possible alternative forms that can be pursued. In the case of suspensions, there are many challenges such as shelf-life stability. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0006] In one aspect, (i) ibrutinib, which is a compound having a structure of Compound 1

Chemical formula

[0007] The formulations of the present invention may be reconstitutable, i.e., they may contain no pharmaceutically acceptable carrier (e.g., purified water or another suitable carrier as defined herein), or they may be suspension products that already contain a carrier (e.g., purified water or another suitable carrier as defined herein). Thus, in the latter case, (i) Ibrutinib, a compound having the structure of

Chemical formula

[0008] Accordingly, the present invention relates to various formulations that are suspensions containing ibrutinib or a pharmaceutically acceptable salt or solvate thereof, with benzyl alcohol being the main preservative present, and the formulations may further contain one or more additional pharmaceutically acceptable excipients. The present invention further relates to methods of preparing such pharmaceutical formulations. The present invention further relates to the use of such formulations as medicaments, for example, in the treatment of diseases described hereinafter in this specification. The present invention also relates to a method of treating a disease in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of such a pharmaceutical formulation.

[0009] In this specification, it is shown that benzyl alcohol is the main preservative present in the formulations of the present invention, which is understood by those skilled in the art to include suitable equivalents of benzyl alcohol that achieve the same effect, having the same or similar effectiveness with respect to preservation, having the same or similar stability profiles, and / or not forming co-crystals with the active ingredient (ibrutinib). All of the above can be tested in the tests used in the experimental section described later in this specification. For example, sufficient preservation can be tested as described in the PET (Preservative Effectiveness Test) described in this specification, and when, for example, the following organisms are employed, it can bring about a reduction of more than 4 logs after 28 days: A. brasilensis, C. albicans, P. aeruginosa, S. aureus and / or E. coli (for example, at the initial concentrations of the organisms as shown in the experimental section below). Stability can be tested as described in the tests in the experimental section (1-month, 2-month, and 6-month stability tests under specific conditions). The formation of co-crystals can also be tested by observing under the conditions described in the experimental section later described in this specification.

[0010] The present invention can be more readily understood by reference to the following description, which is to be construed in relation to the accompanying examples that all form part of the disclosure. The present invention is not limited to the specific products, methods, conditions or parameters described and / or shown herein, and it is to be understood that the terminology used herein is for the purpose of describing specific embodiments by way of example only and is not intended to limit any claimed invention of the present invention. Similarly, any explanation regarding possible mechanisms or modes of action or reasons for improvement, unless otherwise specified, is intended to be illustrative only, and the present invention herein is not bound by the accuracy or inaccuracy of such proposed mechanisms or modes of action or reasons for improvement. Throughout this specification, it is recognized that the description relates to both the characteristics of the formulations described herein and the methods of manufacture and use.

[0011] When ibrutinib is mentioned in this specification, the above-mentioned Compound 1 or its pharmaceutically acceptable salt or solvate described hereinafter in this specification is mentioned. Further, ibrutinib (or its pharmaceutically acceptable salt or solvate) is the active ingredient in the formulations of the present invention and is present in a therapeutically effective amount. For example, in one aspect, when the formulation is intended for a pediatric population, 70 mg of the active ingredient ibrutinib may be present in the formulation (however, if ibrutinib is in salt form, for example, a larger mass may be present). However, in one embodiment, in an aspect of the present invention, the form of ibrutinib used is not a salt or solvate but the free form.

[0012] In one aspect, the ibrutinib in the formulations of the present invention is used in its non-salt form. In another aspect, the ibrutinib used in the formulations of the present invention is, for example, Crystal Form A described and prepared in the pamphlet of International Publication No. WO 2013 / 184572 of the international patent application.

[0013] In the formulations of the present invention, the active pharmaceutical ingredient ibrutinib (or a salt / solvate thereof) may be present in a therapeutically effective and suitable amount. The formulations of the present invention include suspensions, in which case the suspension preferably contains as much ibrutinib (or a salt / solvate thereof) as can be tolerated in the presence of a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutically acceptable carrier (if present) is an aqueous solution, and in a particular embodiment, this is water, such as purified water or sterile water. However, the carrier can be selected from water (e.g., tap water, purified water or sterile water), ethanol, propylene glycol, glycerol, polyethylene glycol, etc., or any combination thereof; for example, in one embodiment, the carrier contains up to 90% water and the remainder is any of the other aforementioned carriers such as ethanol, and in another embodiment, the carrier contains at least 90% water (and up to 10% of the remainder contains one or more of the other aforementioned carriers). In a further embodiment, the amount of ibrutinib can be present in an amount of 1 w / v% to 20 w / v%, such as about 2 w / v% to 15 w / v%, and in one embodiment, this can be present in an amount of about 3 w / v% to 10 w / v%, such as about 7 w / v%, and when this relates to a formulation that is a suspension, the carrier (e.g., purified water) is intended to be within the w / v ratio, and when this relates to a formulation (e.g., a powder) for reconstitution, the w / v ratio takes into account the amount of carrier (or liquid such as water) to which addition is intended (or will be made). Thus, in one embodiment, ibrutinib (or a salt / solvate thereof) is present in an amount of about 20 mg / ml to 150 mg / ml, and in a further embodiment about 30 mg / ml to 100 mg / ml, about 60 mg / ml to 80 mg / ml, such as about 70 mg / ml.

[0014] When the ratio is stated as w / v in this specification and the amount is stated in units of mg / ml (or mg / ml used interchangeably in this specification), the volume is understood to include the carrier (e.g., purified water) when the formulation of the present invention is a suspension, and when the formulation of the present invention is for reconstitution (e.g., powder), the w / v ratio and mg / ml include the carrier (or liquid such as water) to which addition is intended (or will be added). In these cases, the carrier or pharmaceutically acceptable carrier may also be referred to as a diluent. The carrier can be water, and in the case of a suspension, it is preferably purified water (otherwise the shelf life may be affected), and also, for example, in the case of a powder for reconstitution, this can be purified water, but it can also be drinking water (e.g., tap water).

[0015] It is shown herein that at least one preservative that is benzyl alcohol is present in the formulations of the present invention. Thus, for example, one or more other preservatives selected from the following list may be present. However, in one embodiment, the preservative of the formulation of the present invention comprises more than 25%, for example more than 50% (by weight) benzyl alcohol, and even in this case, the formulation may further contain other preservatives other than benzyl alcohol, such as the other preservatives described below (provided that the total weight percentage of the other preservatives does not exceed 75% or 50% as required). In one aspect, the preservative in the formulation of the present invention comprises more than 70% benzyl alcohol, for example more than 90% benzyl alcohol, and in one aspect, the preservative consists essentially of benzyl alcohol (i.e., the preservative of the formulation of the present invention is more than 99% or about 100% benzyl alcohol and the other preservatives are less than 1% or essentially absent). This is because, as explained below, the presence of benzyl alcohol is unexpectedly advantageous compared to other preservatives. This is extremely important for the suspension to have adequate stability, and achieving this remains a challenge. However, using benzyl alcohol as a preservative may have the following associated benefits: (i) the shelf life of the formulation of the present invention; (ii) the stability of the formulation (e.g., physical stability) and its bactericidal activity (e.g., as measured by PET (Preservative Efficacy Test)); (iii) reduced formation of undesirable co-crystals and other visible impurities or spots in the suspension that may occur due to insufficient dispersion of by-products, such as precipitates or particles (e.g., ibrutinib particles) in the formulation / suspension. Such visible impurities or spots are signs of agglomerate formation and thus signs of instability.

[0016] As described herein, the formulations of the present invention contain one or more other preservatives in addition to benzyl alcohol (however, in one embodiment, the preservative is solely benzyl alcohol), and in this regard, the preservative may include one or more of an antibacterial agent, an antioxidant, a free radical scavenger, an oxygen scavenger, and / or a chelating agent. For example, the antibacterial agent and antioxidant may be selected from the group consisting of benzoic acid, parabens (e.g., methyl or ethyl paraben), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorobutanol, gallate, hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-γ-picolinium chloride, phenylmercuric acetate, thimerosal, sorbic acid, and propionic acid (and propylene glycol may also be mentioned). Examples of free radical scavengers include BHA, BHT, vitamin E, and ascorbyl palmitate, and mixtures thereof. Examples of oxygen scavengers include sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine, methionine, thioglycerol, sodium acetone bisulfite, isoascorbic acid, and hydroxypropyl cyclodextrin. Examples of chelating agents include sodium citrate, sodium EDTA, and malic acid. Other preservatives that may be mentioned include acetic acid (e.g., those that may act as an antioxidant or chelating agent), etc. In one embodiment, the other preservative is not an oxygen scavenger, and in a further embodiment, the other preservative is an antibacterial agent and / or an antioxidant. In one embodiment of the present invention, the formulations of the present invention do not contain preservatives other than benzyl alcohol.

[0017] For example, the amount of preservative may be present in an amount of 0.1 w / v% to 10 w / v%, such as about 0.1 w / v% to 5 w / v%, and in one embodiment may be present in an amount of about 0.5 w / v% to 2 w / v%, such as about 1 w / v%. Thus, in one embodiment, the preservative is present in an amount of about 1 mg / ml to 50 mg / ml, and in a further embodiment, in an amount of about 2 mg / ml to 25 mg / ml, about 5 mg / ml to 20 mg / ml, such as about 10 mg / ml. As shown herein, the formulations of the present invention contain a preservative that is benzyl alcohol, and in one embodiment, this contains at least about 0.1 w / v% or at least about 1 mg / ml of benzyl alcohol, and in a further embodiment, this contains at least about 0.5 w / v% or at least about 5 mg / ml of benzyl alcohol. For example, herein, when it is stated that the preservative contains more than 50% benzyl alcohol, specifically, when 1 w / v% of the preservative is present, this is to be interpreted as 0.5 w / v% benzyl alcohol and 0.5 w / v% of one or more other preservatives (e.g., as described above herein). However, in one aspect, since the preservative is shown to consist essentially of benzyl alcohol, the ranges described herein specifically apply to the amount of benzyl alcohol present (e.g., about 0.5 w / v% to 2 w / v% or about 5 mg / ml to 20 mg / ml of benzyl alcohol), and in this aspect there are substantially no other preservatives present in the formulations of the present invention.

[0018] As shown, the formulation of the present invention can be a suspension. Thus, in one aspect, the formulation of the present invention includes a further excipient that is a suspending agent. A suspending agent can be any substance that promotes the suspension or dispersion of particles and / or reduces the precipitation or accumulation (or aggregation) of particles at points within the suspension. The suspending agent can increase the viscosity and also promote sufficient surface activity (for example, if it is also a wetting agent). In this regard, the suspending agent can be one or more of the following agents: alginates, cellulose ethers, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, acacia, tragacanth, xanthan gum, bentonite, carbomers, carrageenan, powdered cellulose, and gelatin. Other suspending agents that may be mentioned include hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC); such agents can serve as suspending agents and wetting agents, but in one embodiment where the wetting agent is selected from HPMC and / or HPC, the suspending agent is not the same.

[0019] In one aspect, suspending agents that can be used in the formulations of the present invention include carrageenan, xanthan (or xanthan gum; e.g., any suitable polysaccharide produced by fermentation of carbohydrates by Gram-negative bacteria) or cellulose ethers (e.g., any suitable cellulose ether usually produced by etherification of alkali cellulose). In one aspect, a formulation of the present invention is provided, wherein the suspending agent is a cellulose ether, such as microcrystalline cellulose and / or sodium carboxymethyl cellulose (e.g., a suspending agent available under the trade name Avicel®), and can be selected based on its suitability for use in suspensions where shelf-life stability is desired. One of ordinary skill in the art will understand that when microcrystalline cellulose and / or sodium carboxymethyl cellulose are used as suspending agents, an optimal form is preferred. For example, in one embodiment, the formulation of the present invention can be a reconstitutable suspension, or in another embodiment, the formulation can already contain a pharmaceutically acceptable carrier (e.g., purified water), and in each of these cases, there may be an Avicel® product that is more suitable for each embodiment.

[0020] In some embodiments, the suspending agent is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methylcellulose, methylcellulose (e.g., Methocel®), croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linked croscarmellose, cross-linked starch, such as sodium starch glycolate, cross-linked polymers, such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, and rubber. In one embodiment, starch is not used as a suspending agent because it can increase the viscosity excessively beyond what is desired.

[0021] The microcrystalline cellulose that can be used as a suspending agent in the formulation of the present invention can be derived from any suitable source. For example, it can be silicated microcrystalline cellulose (SMCC) such as SMCC HD90 (e.g., PROSOLV SMCC (registered trademark) available from JRS Pharma), or it can be a mixture of microcrystalline cellulose and sodium carboxymethylcellulose (e.g., commercially available under the trade name Avicel (registered trademark)).

[0022] The amount of the suspending agent can be present in an amount of 0.1 w / v% to 10 w / v%, for example, about 0.1 w / v% to 5 w / v%. In one embodiment, it can be present in an amount of about 0.5 w / v% to 2 w / v%, for example, about 1.2 w / v%. Thus, in one embodiment, the suspending agent is present in an amount of about 1 mg / ml to 50 mg / ml, and in a further embodiment, in an amount of about 2 mg / ml to 25 mg / ml, about 5 mg / ml to 20 mg / ml, for example, about 12 mg / ml. In one embodiment, the suspending agent is an essential component of the formulation of the present invention.

[0023] The formulations of the present invention may also contain other excipients or carriers. For example, in one aspect, the formulations of the present invention may further contain a wetting agent or surfactant, and typical examples include those that reduce surface tension, such as those selected from the following list: gelatin, casein, lecithin, salts of charged phospholipids or their acid forms (phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid and their salts such as their alkali metal salts, for example their sodium salts, such as egg phosphatidylglycerol sodium available under the trade name Lipoid(™) EPG), gum arabic, stearic acid, benzalkonium chloride, polyoxyethylene alkyl ethers, such as macrogol ethers, such as cetomacrogol 1000, polyoxyethylene castor oil derivatives; polyoxyethylene stearate, colloidal silicon dioxide, sodium dodecyl sulfate, sodium carboxymethyl cellulose, bile salts, such as sodium taurocholate, sodium desoxytaurocholate, sodium desoxycholate; methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium aluminate silicate, polyvinyl alcohol (PVA), poloxamers which are block copolymers of ethylene oxide and propylene oxide such as Pluronic(™) F68, F108 and F127; tyloxapol; vitamin E-TGPS (α-tocopheryl polyethylene glycol succinate, specifically α-tocopheryl polyethylene glycol 1000 succinate); poloxamine, such as Tetronic(™) 908 (T908) which is a tetrafunctional block copolymer derived from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine; dextran; lecithin; dioctyl ester of sodium sulfosuccinate, such as the product commercially available under the trade name Aerosol OT(™) (AOT); sodium lauryl sulfate (Duponol(™) P); alkylaryl polyether sulfonate available under the trade name Triton(™) X-200; polyoxyethylene sorbitan fatty acid esters (Tweens(™) 20, 40, 60 and 80);Sorbitan esters of fatty acids (Span (trademark) 20, 40, 60 and 80 or Arlacel (trademark) 20, 40, 60 and 80); polyethylene glycol (e.g., those commercially available under the trade names Carbowax (trademark) 3550 and 934); sucrose stearate and sucrose distearate mixtures, e.g., products available under the trade names Crodesta (trademark) F110 or Crodesta (trademark) SL-40; hexadecyltrimethylammonium chloride (CTAC); polyvinylpyrrolidone (PVP); nonionic surfactants, e.g., polyethoxylated castor oil (e.g., commercially available under the trade name Kolliphor). Optionally, two or more wetting agents and / or surfactants can be used in combination.;

[0024] In one aspect, the wetting agent or surfactant is a water-soluble polymer derived from a cellulose ether such as cellulose, e.g., hydroxypropyl cellulose (HPC including various commercial products) or hydroxypropyl methylcellulose (e.g., commercial product HPMC2208). As indicated above, the suspending agent can overlap with the wetting agent, and in this regard, in one aspect, the wetting agent (if present) is different from the surfactant. Thus, if both the suspending agent and the wetting agent are cellulose ethers, in one embodiment, these are different cellulose ethers (e.g., the suspending agent can be microcrystalline cellulose and / or sodium carboxymethyl cellulose, and the wetting agent can be HPMC).

[0025] In one aspect, a surfactant / wetting agent is present in the formulation of the present invention. The amount of such an agent can be present in an amount of 0.05 w / v% to 10 w / v% or 0.05 w / v% to 5 w / v% (for example, 0.05 w / v% to 2 w / v%), for example, in an amount of about 0.05 w / v% to 1 w / v%, and in one embodiment, it can be present in an amount of about 0.1 w / v% to 0.5 w / v%, for example, about 0.25 w / v%. Thus, in one embodiment, the surfactant / wetting agent is present in an amount of about 0.5 mg / ml to 100 mg / ml or 0.5 mg / ml to 50 mg / ml (for example, 0.5 mg / ml to 20 mg / ml), and in a further embodiment, it is present in an amount of about 0.5 mg / ml to 10 mg / ml, about 1 mg / ml to 5 mg / ml, for example, about 2.5 mg / ml. In one embodiment, the wetting agent (or surfactant) is an essential component of the formulation of the present invention.

[0026] In one embodiment, the formulation of the present invention may optionally contain one or more buffers and / or pH adjusters. This is because, in one aspect of the present invention, the pH of the formulation of the present invention is preferably in the range of about pH 4 to pH 8 (for example, pH 5 to pH 7), specifically about pH 6. A buffer solution or buffer is typically a mixture of two components, such as a weak acid and its conjugate base or a weak base and its conjugate acid. For example, in this context, components of the buffer solution or buffer that can be used can include salts of weak acids. In one aspect, the buffer contains citric acid (such as citric acid.H2O; this can be pre-formed or formed during the process of preparing the formulation of the present invention) and sodium hydrogen phosphate (for example, disodium hydrogen phosphate or sodium dihydrogen phosphate, Na2HPO4 or NaH2PO4 respectively), and in another aspect, the pH adjuster can be a strong acid or strong base such as sodium hydroxide (NaOH) and / or hydrochloric acid (HCl). Therefore, examples of components of the buffer (buffer solution) and pH adjuster include, including mixtures thereof, tartaric acid, maleic acid, glycine, sodium lactate / lactic acid, ascorbic acid, sodium citrate / citric acid, sodium acetate / acetic acid, sodium bicarbonate / carbonic acid, sodium succinate / succinic acid, sodium benzoate / benzoic acid, sodium phosphate, tris(hydroxymethyl)aminomethane, sodium bicarbonate / sodium carbonate, ammonium hydroxide, benzenesulfonic acid, sodium benzoate / acid, diethanolamine, glucono-delta-lactone, hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic acid, glyceric acid, glutaric acid, glutamic acid, ethylenediaminetetraacetic acid (EDTA), triethanolamine, one or more of which are mentioned. In one embodiment, examples of the formulation of the present invention include buffers containing components such as weak acids or preferably inorganic salts of acids, such as citric acid and / or phosphates (for example, sodium hydrogen phosphate such as NaH2PO4 or preferably Na2HPO4). As used herein, when citric acid is mentioned in relation to components of the buffer solution / buffer, citric acid hydrate, that is, citric acid and water in a 1:1 ratio (citric acid.H2O) is cited (because citric acid itself is hygroscopic in other cases).

[0027] In one aspect, the total amount of buffer (or buffering agent) present in the formulation of the present invention is in an amount of 0.05 w / v% to 2 w / v%, for example about 0.05 w / v% to 1 w / v%, and in one embodiment may be present in an amount of about 0.1 w / v% to 0.5 w / v%, for example about 0.2 w / v%. Thus, in one embodiment, the buffering agent is present in an amount of about 0.5 mg / ml to 20 mg / ml, and in a further embodiment in an amount of about 0.5 mg / ml to 10 mg / ml, about 1 mg / ml to 5 mg / ml, for example about 2 mg / ml (or present in an amount of about 2 mmol / ml to 150 mmol / ml, for example 5 mmol / ml to 30 mmol / ml, for example about 15 mmol / ml; whereby, when citric acid hydrate and Na2HPO4 are used, the amounts can be about 3 to 4 mmol / ml and 9 to 11 mmol / ml respectively). In one embodiment, the buffering agent (or a mixture containing two or more buffering agents) is an essential component of the formulation of the present invention, and in one aspect, this contains citric acid (citric acid.H2O) and sodium phosphate (for example, disodium hydrogen phosphate (Na2HPO4)) in a ratio of, for example, 1:3 to 3:1 relative to mg / ml (for example, about 1:2 to 2:1, for example about 1:1), however, the ratio is preferably about 1:2 (as shown relative to mg / ml; conversion to molar ratio can also be determined, for example, relative to mmol / ml, and the ratio can be 1:5 to 1:1, for example about 1:4 to 1:2, for example about 1:3). Thereafter, the formulation of the present invention may further comprise acids and bases for pH adjustment purposes, such as the strong acid and / or strong base pH adjusters described above herein; for example, q.s. NaOH and / or HCl may be added to the formulation of the present invention for a desired pH (for example, pH 6.0 ± 0.1). Purified water may also be added for this purpose and also exists as a pharmaceutically acceptable carrier (or solvent) and is added q.s. based on the w / v ratios provided herein.

[0028] In one aspect, the formulation of the present invention may optionally contain a sweetening agent. Sweetening agents such as natural or artificial sweeteners or combinations thereof may be included in the formulations described herein. In one embodiment, the natural sweetener is sucrose including raw sugar, granulated sugar, brown sugar, confectionery sugar and soft sugar, fructose, honey, fruit sugar, high fructose corn syrup, corn syrup, mannitol, sorbitol, xylitol, erythritol and other sugar alcohols, hydrolyzed hydrogenated starch, lactitol or maltitol, osmalto, dextrose, invert sugar, agave nectar, glucose, lactose, maltose, maple sugar, date 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 a further embodiment, the sweetening agent is sucralose.

[0029] When the sweetening agent is present in the formulation of the present invention, the total amount present is in an amount of 0.01 w / v% to 1 w / v%, for example about 0.05 w / v% to 0.5 w / v%, and in one embodiment about 0.05 w / v% to 0.2 w / v%, for example about 0.1 w / v%. Thus, in one embodiment, the sweetening agent is present in an amount of about 0.1 mg / ml to 10 mg / ml, and in a further embodiment about 0.5 mg / ml to 5 mg / ml, about 0.5 mg / ml to 2 mg / ml, for example about 1 mg / ml.

[0030] The amounts of the components of the formulation of the present invention may be in specific ratios as specified below: Ibrutinib - 70 mg / ml Benzyl alcohol preservative - 10 mg / ml Suspending agent - 12 mg / ml Wetting agent - 2.5 mg / ml Buffer - 2.1 mg / ml Sweetening agent - 1 mg / ml pH adjuster (e.g., NaOH and / or HCl), q.s., ad pH 6.0 ± 0.1 Pharmaceutical carrier - Purified water, q.s.ad 1 ml.

[0031] The formulation of the present invention is a suspension and thus, in one aspect, has a pharmaceutically acceptable carrier which is purified water. The amounts of the components of the formulation are presented herein as relative (w / v) to 1 ml of the carrier (purified water). Thus, a predetermined volume of the suspension can be used to administer a specific dose. In this regard, the suspension can be of a lower concentration or a higher concentration. If the suspension is of a lower concentration, the relative amounts (w / v) of the active ingredients can vary such that they are halved (for example, 70 mg of ibrutinib can be present in 2 ml of purified water or 35 mg of ibrutinib can be present in 1 ml of purified water). In this case, the remaining components can also be adjusted accordingly, but preferably, these remain the same, i.e., for any remaining components (when present) such as benzyl alcohol, suspending agent, wetting agent, buffer, sweetening agent and pH adjuster, their amounts (in units of mg / ml or w / v) as measured relative to 1 ml of the carrier (for example, purified water) as referred to herein with respect to the formulation of the present invention are also applicable here (for example, 10 mg / ml of benzyl alcohol per 1 ml of the carrier). If 35 mg of API (ibrutinib) is present per ml and a 70 mg dose is desired, 2 ml will be the predetermined volume of the suspension (assuming, for example, that 35 mg of ibrutinib is present per ml). The suspension can also be of a higher concentration, in which case the relative amount of the API (ibrutinib) can vary such that they are doubled, for example, to 140 mg of ibrutinib in 1 ml of purified water, in which case, for a 70 mg dose, 0.5 ml will be the predetermined volume. If the suspension is of a higher concentration, again, the remaining components can be adjusted accordingly, but preferably, these remain the same, i.e., for any remaining components (when present) such as benzyl alcohol, suspending agent, wetting agent, buffer, sweetening agent and pH adjuster, their amounts (in units of mg / ml or w / v) as measured relative to 1 ml of the carrier (for example, purified water) as referred to herein with respect to the formulation of the present invention are also applicable here. Therefore, the formulation or suspension of the present invention can be of a lower concentration or a higher concentration and thus, the predetermined volume of the formulation / suspension is adjusted accordingly.In this regard, the formulations of the present invention can be adjusted for the API present (ibrutinib) and can be in the range of 7 mg / ml to 700 mg / ml in 1 ml of carrier, or can be in any of the other ranges mentioned herein (e.g., 20 - 200 mg / ml, etc.).

[0032] Although w / v (generally regarding the weight of a component relative to the volume of the carrier, e.g., the volume of purified water) is described herein, it will be understood that the present invention described herein can also be described in terms of the relative weights of the components of the formulations / suspensions described herein relative to each other. In such cases, a pharmaceutically acceptable carrier (e.g., purified water) can be present in a volume range based on the weight of the components, e.g., this can be 1 ml per 70 mg of ibrutinib (as described herein for a particular embodiment), while it can be any other feasible dilution, e.g., 1 ml per 10 mg of ibrutinib and 1 ml per 210 mg of ibrutinib (e.g., 1 ml per 35 mg of ibrutinib and 1 ml per 140 mg of ibrutinib). In such cases, the amounts of all other components of the formulations / suspensions of the present invention are adjusted accordingly. For example, in one aspect, a formulation of the present invention is provided, and the relative amounts (w / w) of the components (relative to each other) and compared to 70 mg of ibrutinib are as follows: 5 - 15 mg of benzyl alcohol preservative; 6 - 18 mg of suspending agent; Optionally, e.g., 1 - 5 mg of wetting agent; Optionally, e.g., 1 - 3 mg of buffer; Optionally, e.g., 0.2 - 2 mg of sweetening agent; and Optionally pH adjuster (q.s.) is as follows, and a pharmaceutically acceptable carrier (e.g., purified water) is present in a predetermined amount as described herein (e.g., 1 ml per 10 mg of ibrutinib to 1 ml per 210 mg of ibrutinib, e.g., about 1 ml per 70 mg of ibrutinib). In these cases, the suspending agent, wetting agent, buffer, sweetening agent, and pH adjuster can be any of those described herein (e.g., specific ones) in the embodiments of the present invention. In this regard, the following formulation is one embodiment of the present invention, and the relative amounts (w / w) of the components compared to 70 mg of ibrutinib are as follows: 8 - 12 mg of benzyl alcohol preservative; 10 - 14 mg of a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., Avicel®); Optionally 2 - 3 mg of hydroxypropyl methylcellulose (HPMC); Optionally 1.5 - 2.5 mg of citrate.H2O and / or a phosphate such as sodium hydrogen phosphate; Optionally 0.5 - 1.5 mg of sucralose; and Optionally NaOH and / or HCl (q.s.) for adjusting the pH, is as follows, and as shown above, a pharmaceutically acceptable carrier (e.g., purified water) is present in a predetermined amount as described herein (e.g., 1 ml per 10 mg of ibrutinib to 1 ml per 210 mg of ibrutinib, e.g., about 1 ml per 70 mg of ibrutinib).

[0033] As described herein, the formulations of the present invention contain a pharmaceutical carrier such as purified water. Accordingly, the dose is administered as a fixed volume of suspension. As described herein, when the dose is 70 mg of ibrutinib, the amount of the carrier (e.g., purified water) is 1 ml. As shown herein, the suspension can be of a lower concentration or a higher concentration, but in any case, the volume of the suspension required for a specific dose is predetermined.

[0034] In a further aspect of the present invention, the components of the formulation of the present invention can be any one of the following ratios based on a pharmaceutical carrier that is 1 ml of purified water: 20 - 200 mg / ml of ibrutinib; 2.5 - 25 mg / ml of benzyl alcohol preservative; 2 - 24 mg / ml of suspending agent; optionally, for example, 0.5 - 10 mg / ml of wetting agent; optionally, for example, 0.5 - 10 mg / ml of buffer; optionally, for example, 0.1 - 5 mg / ml of sweetening agent; and optionally pH adjuster (q.s.); 40 - 100 mg / ml of ibrutinib; 5 - 15 mg / ml of benzyl alcohol preservative; 6 - 18 mg / ml of suspending agent; optionally, for example, 1 - 5 mg / ml of wetting agent; optionally, for example, 1 - 3 mg / ml of buffer; optionally, for example, 0.2 - 2 mg / ml of sweetening agent; and optionally pH adjuster (q.s.); or 60 - 80 mg / ml of ibrutinib; 8 - 12 mg / ml of benzyl alcohol preservative; 10 - 14 mg / ml of suspending agent; optionally, for example, 2 - 3 mg / ml of wetting agent; optionally, for example, 1.5 - 2.5 mg / ml of buffer; optionally, for example, 0.5 - 1.5 mg / ml of sweetening agent; and optionally pH adjuster (q.s.).

[0035] In certain embodiments, the formulation of the present invention has the specified components (e.g., as described in the aspects of the present invention above herein), for example, the suspending agent is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., trademark Avicel®, e.g., commercially available as Avicel® RC - 591); the wetting agent is hydroxypropyl methylcellulose (HPMC); the buffer is a phosphate such as citric acid.H2O and / or sodium hydrogen phosphate (e.g., a mixture of two in the ratios described herein); the sweetening agent is sucralose; and / or the pH adjuster is NaOH and HCl.

[0036] Accordingly, in certain aspects of the present invention, the following formulations of the present invention are included: 60 - 80 mg / ml of ibrutinib; 8 - 12 mg / ml of benzyl alcohol preservative; 10 - 14 mg / ml of a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., Avicel®); Optionally 2 - 3 mg / ml of hydroxypropyl methylcellulose (HPMC); Optionally 1.5 - 2.5 mg / ml of phosphate such as citric acid.H2O and / or sodium hydrogen phosphate; Optionally 0.5 - 1.5 mg / ml of sucralose; and Optionally NaOH and / or HCl (q.s.) for adjusting the pH.

[0037] In one embodiment, the formulation of the present invention also contains a wetting agent (e.g., HPMC; e.g., in the amounts described herein). In one embodiment, the formulation also contains a buffer (e.g., citric acid.H2O and / or sodium hydrogen phosphate; e.g., in the amounts described herein). In one embodiment, the formulation also contains a sweetening agent (e.g., sucralose; e.g., in the amounts mentioned herein). In one embodiment, NaOH and / or HCl are added to the formulation of the present invention to adjust the pH. The pH can be within any suitable range that allows (or maintains) an appropriate shelf life for the formulation, which is particularly important for suspensions and is also the main reason why the choice of preservative is important. To achieve the desired pH, appropriate adjustment with, for example, NaOH and / or HCl can be attempted. In one aspect, the pH of the formulation / suspension of the present invention is about pH 3 - pH 9, but in further embodiments, the pH is about pH 4 - pH 8 (e.g., about pH 5 - pH 7, e.g., about pH 5.5 - pH 6.5). In one aspect, the pH of the formulation / suspension described herein is adjusted to about pH 6.

[0038] An important aspect of the present invention is shown herein to be the presence of benzyl alcohol as a preservative. This is because benzyl alcohol was the most suitable preservative, as described herein including the examples and tests conducted. For example, co-crystallization with API (ibrutinib) was not observed exceptionally.

[0039] The formulations / suspensions of the present invention are those in which the particle size distribution (PSD) remains within a specific threshold. The formulations / suspensions of the present invention can be advantageous compared to others, even considering that the PSD remains within a specific threshold over time and under specific stress conditions (e.g., temperature and various other storage conditions).

[0040] In one embodiment, suitable agitation is used in the process of preparing the suspensions described herein to ensure that the API (ibrutinib) is evenly dispersed throughout the pharmaceutically acceptable carrier (e.g., purified water). By evenly dispersed, it means that, for example, if not shaken, the suspension may have a gel-like texture, so after shaking (or gentle agitation), the API particles (i.e., ibrutinib particles) disperse or spread / distribute throughout the carrier (e.g., water) of the suspension. This results in any equal portions of the carrier (e.g., water) containing approximately equal amounts of API (ibrutinib) particles (by weight), by which we mean within a deviation of ±25%, preferably ±15% and particularly ±10% (or less, e.g., within ±5%). Thus, when 700 mg of ibrutinib is dispersed in 10 ml of water, each portion of 2.5 ml of water (if divided) should contain approximately 175 mg of ibrutinib, but there is a possibility of a deviation of ±25% (i.e., ±43.75 mg), preferably ±15% (i.e., ±26.25 mg) and particularly ±10% (i.e., ±17.5 mg), and most preferably the deviation is ±5% (i.e., ±8.75 mg). Thus, the suspension is physically substantially uniform or homogeneous throughout the carrier (e.g., aqueous medium) in which it is placed (e.g., after the time required for dispersion by agitation; see above). The larger the volume of water per mg of active ingredient, the more likely the deviation regarding dispersion can be smaller.

[0041] The formulation of the present invention may also have an active ingredient (API), i.e., ibrutinib, having a specific particle size and also a specific particle size distribution (PSD). For example, d v 50 is, in one embodiment, less than 100 μm, for example less than 25 μm.

[0042] Furthermore, in connection with the present invention, in certain embodiments, - d v 10 is less than 5 μm (preferably less than 2 μm, for example less than 1.5 μm, for example around 1.0 or 1.1 μm (or even less than this), and - d v 50 is less than 10 μm (preferably less than 8 μm, for example less than 6 μm, for example around 4 - 5 μm (or even less than this), and - d v 90 is less than 20 μm (preferably less than 15 μm, for example less than 10 μm, for example around 8 - 9 μm (or even less than this).

[0043] As used herein, the term d 50 (or d v 50 ) has its customary meaning known to those skilled in the art and can be measured by particle size measurement techniques known in the art, such as sedimentation field-flow fractionation, photon correlation spectroscopy, laser diffraction, or disc centrifugation. The d v 50 referred to herein may be related to the volume distribution of the particles. In that case, "d v 50 of 5 μm" means that at least 50% of the volume of the particles has a particle size less than 5 μm. The same applies to the other particle sizes mentioned, and d v 10 and d v 90 have a similar meaning. Usually, the same or approximately the same value is obtained for the average particle size from the volume distribution and the weight distribution.

[0044] In connection with the present invention, the formulations (e.g., suspensions) of the present invention described herein may have the advantage that the particle size distribution (PSD) is maintained optimally and thus does not affect the quality of the product.

[0045] It should be recognized that there may be an overlap between the additives (such as excipients / diluents) used in the formulations (e.g., suspensions) described herein, since a given additive is often classified differently by different practitioners on site or is used commonly for any of several different functions. Accordingly, the additives referred to herein should be regarded as merely illustrative of the types of additives that may be included in the formulations described herein and not as limiting. The amount of such additives can be readily determined by one of ordinary skill in the art according to the particular desired properties.

[0046] In another aspect, a method of treating a disease in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein.

[0047] In another aspect, there is provided a method of treating a hematological malignancy in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or formulation described herein. In some embodiments, the cancer is a B-cell proliferative disorder. In some embodiments, the B-cell proliferative disorder is diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia. In some embodiments, the cancer is a B-cell malignancy. In some embodiments, the cancer is a B-cell malignancy selected from chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma. In some embodiments, the cancer is a lymphoma or leukemia. In some embodiments, the cancer is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis.

[0048] In another aspect, there is provided a process for preparing a pharmaceutical composition or formulation (e.g., as described herein) comprising ibrutinib, the process comprising mixing the components of the composition / formulation with each other. In one aspect, an essential preservative, which is benzyl alcohol, is added first, followed by the addition of other components of the composition / formulation of the present invention (e.g., carrier, ibrutinib, and suspending agent, etc.), and in a further specific aspect, the composition / formulation can be prepared as described in the following examples.

[0049] In another aspect, there is provided herein a method of treating a patient by administering a formulation (e.g., a suspension) described herein that contains Compound 1.

[0050] Other objects, features and advantages of the methods and compositions / formulations described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. The headings of the items used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals and treatises, are hereby expressly incorporated by reference in their entirety for all purposes.

[0051] Incorporation by reference All publications and patent applications cited herein are hereby incorporated by reference in this specification to the extent applicable and relevant.

DETAILED DESCRIPTION OF THE INVENTION

[0052] In some embodiments, the methods described herein can be used for the treatment of cancers such as, but not limited to, B-cell proliferative disorders such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, plasmacytosis, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, and lymphomatoid granulomatosis.

[0053] Hematological malignancies In certain embodiments, disclosed herein is a method of treating a hematological malignancy in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein comprising a certain amount of Compound 1.

[0054] In some embodiments, the hematologic malignancy is non-Hodgkin lymphoma (NHL). In some embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL or non-CLL / SLL lymphoma. In some embodiments, the hematologic malignancy is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, multiple myeloma (MM), marginal zone lymphoma, Burkitt lymphoma, non-Burkitt high-grade B-cell lymphoma or extranodal marginal zone B-cell lymphoma. In some embodiments, the hematologic malignancy is acute or chronic myeloid (or myelocytic) leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia or precursor B-cell acute lymphoblastic leukemia. In some embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, the hematologic malignancy is mantle cell lymphoma (MCL). In some embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is the ABC subtype of diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is the GCB subtype of diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is Waldenström macroglobulinemia (WM). In some embodiments, the hematologic malignancy is multiple myeloma (MM). In some embodiments, the hematologic malignancy is Burkitt lymphoma. In some embodiments, the hematologic malignancy is follicular lymphoma (FL). In some embodiments, the hematologic malignancy is transformed follicular lymphoma. In some embodiments, the hematologic malignancy is marginal zone lymphoma.

[0055] In some embodiments, the hematologic malignancy is relapsed or refractory non-Hodgkin lymphoma (NHL). In some embodiments, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma (MCL), relapsed or refractory follicular lymphoma (FL), relapsed or refractory CLL, relapsed or refractory SLL, relapsed or refractory multiple myeloma, relapsed or refractory Waldenström macroglobulinemia, relapsed or refractory multiple myeloma (MM), relapsed or refractory marginal zone lymphoma, relapsed or refractory Burkitt lymphoma, relapsed or refractory non-Burkitt high-grade B-cell lymphoma, relapsed or refractory extranodal marginal zone B-cell lymphoma. In some embodiments, the hematologic malignancy is relapsed or refractory acute or chronic myeloid (or myeloid) leukemia, relapsed or refractory myelodysplastic syndrome, relapsed or refractory acute lymphoblastic leukemia or relapsed or refractory precursor B-cell acute lymphoblastic leukemia. In some embodiments, the hematologic malignancy is relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the hematologic malignancy is relapsed or refractory mantle cell lymphoma (MCL). In some embodiments, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is the ABC subtype of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is the GCB subtype of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is relapsed or refractory Waldenström macroglobulinemia (WM). In some embodiments, the hematologic malignancy is relapsed or refractory multiple myeloma (MM). In some embodiments, the hematologic malignancy is relapsed or refractory Burkitt lymphoma. In some embodiments, the hematologic malignancy is relapsed or refractory follicular lymphoma (FL).

[0056] In some embodiments, the hematological malignancy is a hematological malignancy classified as high-risk. In some embodiments, the hematological malignancy is high-risk CLL or high-risk SLL.

[0057] B-cell lymphoproliferative disorders (BCLDs) are blood neoplasms, including, inter alia, non-Hodgkin lymphoma, multiple myeloma, and leukemia. BCLDs can originate from either lymphoid tissue (e.g., in the case of lymphoma) or bone marrow (e.g., in the case of leukemia and myeloma), and they are all involved in the uncontrolled proliferation of lymphocytes or white blood cells. There are many subtypes of BCLDs, such as, for example, chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). The disease course and treatment of BCLDs depend on the subtype of BCLD. However, clinical findings, morphological appearance, and response to treatment are heterogeneous even within each subtype.

[0058] Malignant lymphoma is mainly the malignant transformation of cells present within lymphoid tissue. The two groups of malignant lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Both types of lymphoma infiltrate the reticuloendothelial tissue. However, they differ in terms of the origin of the neoplastic cells, the site of the disease, the presence of systemic symptoms, and the response to treatment (Freedman et al., “Non-Hodgkin’s Lymphomas” Chapter 134, Cancer Medicine, (an approved publication of the American Cancer Society, B.C. Decker Inc., Hamilton, Ontario, 2003).

[0059] Non-Hodgkin lymphoma In certain embodiments, disclosed herein is a method of treating non-Hodgkin lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1.

[0060] In certain embodiments, a method of treating a subject having relapsed or refractory non-Hodgkin lymphoma, the method comprising administering to the subject a composition described herein comprising a therapeutically effective amount of Compound 1, is further disclosed herein. In some embodiments, the non-Hodgkin lymphoma is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, or relapsed or refractory CLL.

[0061] Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignancies that are predominantly of B-cell origin. NHL can occur in any organ associated with the lymphatic system, such as the spleen, lymph nodes, or tonsils, and can occur at any age. NHL is often characterized by prominent lymphadenopathy, fever, and weight loss. NHL is classified into either B-cell or T-cell NHL. Lymphomas associated with post-transplant lymphoproliferative disorders of the bone marrow or stem cells are usually B-cell NHL. In the Working Formulation classification scheme, NHLs were classified into low-, intermediate-, and high-grade categories based on their natural history (see “The Non-Hodgkin’s Lymphoma Pathologic Classification Project,” Cancer 49(1982):2112-2135). Low-grade lymphomas are indolent and have an average survival of 5-10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311:1471-1475). Chemotherapy can induce remission in the majority of indolent lymphomas, but cure is rare and most patients ultimately relapse and require further treatment. Intermediate- and high-grade lymphomas are more aggressive tumors but are more likely to be cured with chemotherapy. However, a significant proportion of these patients relapse and require further treatment.

[0062] The list of non-limiting B-cell NHLs includes Burkitt lymphoma (e.g., endemic Burkitt lymphoma and sporadic Burkitt lymphoma), cutaneous B-cell lymphoma, cutaneous marginal zone lymphoma (MZL), diffuse large cell lymphoma (DLBCL), diffuse large and small cell mixed lymphoma, diffuse small cleaved cell, diffuse small lymphocyte lymphoma, extranodal marginal zone B-cell lymphoma, follicular lymphoma, follicular small cleaved cell (grade 1) lymphoma, follicular small cleaved and large cell mixed (grade 2) lymphoma, follicular large cell (grade 3) lymphoma, intravascular large B-cell lymphoma, intravascular lymphomatosis, large cell immunoblastic lymphoma, large cell lymphoma (LCL), lymphoblastic lymphoma, malt lymphoma, mantle cell lymphoma (MCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL) / small lymphocyte lymphoma (SLL), extranodal marginal zone B-cell lymphoma - mucosa-associated lymphoid tissue (MALT) lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, Waldenström macroglobulinemia, and primary central nervous system (CNS) lymphoma. Further non-Hodgkin lymphomas are contemplated to be within the scope of the present invention and will be apparent to those skilled in the art.

[0063] DLBCL In certain embodiments, disclosed herein is a method of treating DLBCL in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1. In certain embodiments, further disclosed herein is a method of treating relapsed or refractory DLBCL in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein).

[0064] As used herein, the term "diffuse large B-cell lymphoma (DLBCL)" refers to a neoplasm of germinal center B lymphocytes having a diffuse growth pattern and a high to intermediate proliferation index. DLBCL accounts for approximately 30% of all lymphomas and can present several morphological variants including the germinal center blast subtype, immunoblast subtype, T-cell / histiocyte-rich subtype, undifferentiated subtype, and plasmablastic subtype. Genetic testing has shown that there are various subtypes of DLBCL. These subtypes appear to have various outcomes (prognoses) and responses to treatment. DLBCL can affect any age group but occurs mainly in the elderly (average age mid-60s).

[0065] In certain embodiments, a method of treating an activated B-cell-like subtype of diffuse large B-cell lymphoma (ABC-DLBCL) in an individual in need thereof is disclosed herein, the method comprising administering to the individual ibrutinib in an amount of from 100 mg / day to 1000 mg / day. The ABC subtype of diffuse large B-cell lymphoma (ABC-DLBCL) is thought to arise from post-germinal center B cells that are arrested during cytoplasmic differentiation. The ABC subtype of DLBCL (ABC-DLBCL) accounts for approximately 30% of all DLBCL diagnoses. This is considered to be the most difficult to cure among DLBCL molecular subtypes, and thus patients diagnosed with ABC-DLBCL typically show a significant decrease in survival rate compared to individuals having other types of DLCBL. ABC-DLBCL is most commonly associated with chromosomal translocations that deregulate the germinal center master regulator BCL6 and mutations that inactivate the PRDM1 gene encoding a transcriptional repressor required for plasma cell differentiation.

[0066] Follicular lymphoma In certain embodiments, disclosed herein is a method of treating follicular lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1. In certain embodiments, disclosed herein is a method of treating relapsed or refractory follicular lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of a formulation described herein).

[0067] As used herein, the term "follicular lymphoma" means any of several types of non-Hodgkin lymphoma in which lymphoma cells cluster into nodules or follicles. The term "follicular" is used because the cells tend to grow in a circular or nodular pattern within lymph nodes. The average age of people with this lymphoma is about 60 years old.

[0068] CLL / SLL In certain embodiments, disclosed herein is a method of treating CLL or SLL in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1. In certain embodiments, disclosed herein is a method of treating relapsed or refractory CLL or SLL in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of a formulation described herein).

[0069] Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL / SLL) are generally considered to be the same disease with slightly different symptoms. Whether it is called CLL or SLL is determined by where the cancer cells gather. If the cancer cells are mainly found in the lymph nodes in the lymphatic system (a system of mainly small blood vessels found in the body) in a nodular form, it is called SLL. SLL accounts for about 5% - 10% of all lymphomas. If most of the cancer cells are present in the bloodstream and bone marrow, it is called CLL.

[0070] Both CLL and SLL are slow-growing diseases, but CLL, which is far more common, tends to grow more slowly. CLL and SLL are treated in the same way. These are generally not considered curable by standard treatment and depend on the stage of the disease and the growth rate, but most patients live longer than 10 years. Sometimes, over time, these slow-growing lymphomas can transform into more aggressive types of lymphoma.

[0071] Chronic lymphocytic leukemia (CLL) is the most common type of leukemia. In the United States, it is estimated that 100,760 people are living with CLL or are in remission from CLL. Most (>75%) of the people newly diagnosed with CLL are over 50 years old. Currently, the treatment of CLL focuses on suppressing the disease and its symptoms rather than achieving a complete cure. CLL is treated by chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms may also be treated surgically (splenectomy for a enlarged spleen) or by radiation therapy ("debulking" of enlarged lymph nodes). CLL generally progresses slowly in most cases but is generally considered incurable. Certain CLL is classified as high-risk. As used herein, "high-risk CLL" means CLL characterized by at least one of 1) 17p13-; 2) 11q22-; 3) unmutated IgVH with ZAP-70+ and / or CD38+; or 4) trisomy 12.

[0072] Typically, CLL treatment is administered when the disease has progressed to the point where it can affect the patient's quality of life, as indicated by the patient's clinical symptoms or blood cell count.

[0073] Small lymphocytic leukemia (SLL) is very similar to the above-mentioned CLL and is also a cancer of B cells. In SLL, abnormal lymphocytes mainly affect the lymph nodes. However, in CLL, abnormal cells mainly affect the blood and bone marrow. The spleen can be affected by both conditions. SLL accounts for approximately 1 / 25 of all cases of non-Hodgkin lymphoma. This can occur at any time from adolescence to old age, but is rare in those under 50 years of age. SLL is considered a chronic lymphoma. That is, the progression of the disease is very slow, and patients tend to live for several years after diagnosis. However, most patients are diagnosed with advanced disease, and although SLL responds well to various chemotherapy agents, it is generally considered incurable. Some cancers tend to occur more frequently in one gender or the other, but cases and deaths due to SLL are evenly divided between men and women. The average age at diagnosis is 60 years.

[0074] SLL is slow but continuously progressive. The normal pattern of this disease is to have disease remission periods and show a high response rate to radiotherapy and / or chemotherapy. After this, recurrence becomes inevitable after several months or years. Response appears again with retreatment, but the disease recurs again. That is, the short-term prognosis of SLL is extremely good, but over time, many patients develop life-threatening complications of recurrent disease. Considering the age of individuals typically diagnosed with CLL and SLL, there is a need in the art for a simple and effective treatment of the disease with minimal side effects that do not interfere with the patient's quality of life. The present invention meets this long-standing need in the art.

[0075] Mantle cell lymphoma In certain embodiments, provided herein is a method of treating mantle cell lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1. In certain embodiments, provided herein is a method of treating relapsed or refractory mantle cell lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of a formulation described herein).

[0076] As used herein, the term “mantle cell lymphoma” refers to a subtype of B-cell lymphoma that arises from CD5-positive antigen-naïve pre-germinal center B cells within the mantle zone that surrounds normal germinal centers. MCL cells generally overexpress cyclin D1 due to a t(11:14) chromosomal translocation of DNA. More specifically, the translocation is present at t(11;14)(q13;q32). Only about 5% of lymphomas are of this type. The cells are small to medium in size. Most often, males are affected. The average age of patients is in the mid-60s. At diagnosis, the lymphoma usually has spread extensively, often including lymph nodes, bone marrow, and in very many cases, the spleen. Mantle cell lymphoma is not a very fast-growing lymphoma, but it is difficult to treat.

[0077] Marginal zone B-cell lymphoma In certain embodiments, provided herein is a method of treating marginal zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1. In certain embodiments, provided herein is a method of treating relapsed or refractory marginal zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of a formulation described herein).

[0078] As used herein, the term "marginal zone B-cell lymphoma" means a group of related B-cell neoplasms that include lymphoid tissue of the marginal zone, which is a patchy area outside the follicular mantle zone. Marginal zone lymphomas account for about 5% to 10% of lymphomas. The cells of this lymphoma appear small under the microscope. There are three main types of marginal zone lymphoma, including extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, and splenic marginal zone lymphoma.

[0079] MALT In certain embodiments, disclosed herein is a method of treating MALT in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1. In certain embodiments, further disclosed herein is a method of treating relapsed or refractory MALT in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of a formulation described herein).

[0080] As used herein, the term "mucosa-associated lymphoid tissue (MALT) lymphoma" means an extranodal manifestation of marginal zone lymphoma. Most MALT lymphomas are of low grade, although a few either present initially as intermediate-grade non-Hodgkin lymphoma (NHL) or progress from a low-grade form. Most MALT lymphomas occur in the stomach, and about 70% of gastric MALT lymphomas are associated with Helicobacter pylori infection. Several cytogenetic abnormalities have been identified, the most common being trisomy 3 or t(11;18). Many of these other MALT lymphomas are also associated with infections by bacteria or viruses. The average age of patients with MALT lymphoma is about 60 years.

[0081] Nodal marginal zone B-cell lymphoma In certain embodiments, provided herein is a method of treating nodal marginal zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1. In certain embodiments, provided herein is a method of treating relapsed or refractory nodal marginal zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of a formulation described herein).

[0082] The term "nodal marginal zone B-cell lymphoma" refers to an indolent B-cell lymphoma found primarily in lymph nodes. This disease is rare, accounting for only 1% of all non-Hodgkin lymphomas (NHL). Most commonly, it is diagnosed in elderly patients and is more prevalent in women than in men. This disease is classified as a marginal zone lymphoma because the mutations occur in the marginal zone of B cells. It is also classified as nodal because it is limited to lymph nodes.

[0083] Splenic marginal zone B-cell lymphoma In certain embodiments, provided herein is a method of treating splenic marginal zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1. In certain embodiments, provided herein is a method of treating relapsed or refractory splenic marginal zone B-cell lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of a formulation described herein).

[0084] The term "splenic marginal zone B-cell lymphoma" refers to a specific low-grade small B-cell lymphoma incorporated into the World Health Organization classification. Its distinctive features are massive splenomegaly, moderate lymphocytosis with a villous morphology, a sinusoidal pattern of involvement of various organs, especially the bone marrow, and a relatively indolent course. Tumor progression with an increase in blast morphology and aggressive behavior is observed in a minority of patients. Molecular and cytogenetic studies have shown heterogeneous results, probably due to the lack of standardized diagnostic criteria.

[0085] Burkitt lymphoma In certain embodiments, disclosed herein is a method of treating Burkitt lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a quantity of Compound 1. In certain embodiments, disclosed herein is a method of treating relapsed or refractory Burkitt lymphoma in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of a formulation described herein).

[0086] The term "Burkitt lymphoma" generally refers to a type of non-Hodgkin lymphoma (NHL) that typically affects children. It is a highly aggressive type of B-cell lymphoma that often initially involves sites in the body other than lymph nodes. Despite its rapid growth, Burkitt lymphoma is often curable with modern intensive therapy. Burkitt lymphoma can be broadly divided into two types, namely sporadic and endemic.

[0087] Endemic Burkitt lymphoma: This disease affects children considerably more often than adults, and 95% of cases are associated with Epstein-Barr virus (EBV) infection. It occurs mainly in equatorial Africa where approximately half of all childhood cancers are Burkitt lymphoma. It characteristically has a high potential for involvement of the jaw as a somewhat differential feature that is rare in sporadic Burkitt. It usually also involves the abdomen.

[0088] Sporadic Burkitt lymphoma: The type of Burkitt lymphoma that affects the rest of the world, including Europe and the continents of North and South America, is the sporadic type. Again, this is mainly a pediatric disease. The association with Epstein-Barr virus (EBV) is not as strong as in endemic cases, but direct evidence of EBV infection is present in 1 in 5 patients. The involvement is greater in the abdomen, where more than 90% of children are significantly affected, than in lymph nodes. Bone marrow involvement is more frequently seen than in sporadic cases.

[0089] Waldenström macroglobulinemia In certain embodiments, disclosed herein is a method of treating Waldenström macroglobulinemia in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1. In certain embodiments, further disclosed herein is a method of treating relapsed or refractory Waldenström macroglobulinemia in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein).

[0090] The term "Waldenström macroglobulinemia," also known as lymphoplasmacytic lymphoma, is a cancer that involves a subtype of white blood cells called lymphocytes. It is characterized by the uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized by lymphoma cells that produce an antibody called immunoglobulin M (IgM). IgM antibodies circulate in large amounts in the blood and thicken the liquid part of the blood like syrup. This can reduce blood flow to many organs, potentially causing visual disturbances (due to poor circulation of blood vessels in the back of the eye) and neuropathy due to poor blood flow in the brain (e.g., headache, dizziness, and confusion). Other symptoms can include feelings of fatigue and weakness and a tendency to bleed easily. The underlying cause is not fully understood, but several risk factors have been identified, including a location on chromosome 6 at 6p21.3. In people with a personal history of autoimmune diseases due to autoantibodies, the risk of developing WM increases 2- to 3-fold, and the risk is particularly high in those associated with hepatitis, human immunodeficiency virus, and rickettsiosis.

[0091] Multiple myeloma In certain embodiments, a method of treating myeloma in an individual in need thereof is disclosed herein, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a defined amount of Compound 1. In certain embodiments, a method of treating relapsed or refractory myeloma in an individual in need thereof is further disclosed herein, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein).

[0092] Multiple myeloma, also known as MM, myeloma, plasmacytic myeloma, or Kahler's disease (after Otto Kahler), is a cancer of white blood cells known as plasma cells. Plasma cells, which are a type of B cell, are a very important part of the immune system that plays a role in antibody production in humans and other vertebrates. They are produced in the bone marrow and transported via the lymphatic system.

[0093] Leukemia In certain embodiments, disclosed herein is a method of treating leukemia in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a certain amount of Compound 1. In certain embodiments, disclosed herein is a method of treating relapsed or refractory leukemia in an individual in need thereof, the method comprising administering to the individual a formulation (e.g., a suspension) described herein that comprises a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein).

[0094] Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase in blood cells, usually white blood cells (leukocytes). Leukemia is a broad term encompassing a range of diseases. A first classification lies between its acute and chronic forms, where (i) acute leukemia is characterized by a rapid increase in immature blood cells. When crowded in this way, the bone marrow is unable to produce healthy blood cells. In acute leukemia, malignant cells grow and accumulate rapidly before spilling into the bloodstream and spreading to other organs of the body, thus requiring urgent treatment. The acute form of leukemia is the most common form of childhood leukemia. (ii) Chronic leukemia is identified by the over-accumulation of relatively mature (although still abnormal) white blood cells. Typically, it progresses over months or years, and the cells are produced at a much faster rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia occurs mainly in the elderly, but theoretically can occur in any age group. In addition, the disease is subdivided according to which type of blood cell is invaded. By this classification, leukemia is divided into lymphoblastic leukemia or lymphocytic leukemia, and myeloid leukemia or myelogenous leukemia. That is, (i) lymphoblastic leukemia or lymphocytic leukemia, in which cancerous changes occur in bone marrow cells that normally continue to form lymphocytes, which are immune system cells that combat infection; (ii) myeloid leukemia or myelogenous leukemia, in which cancerous changes occur in bone marrow cells that normally continue to form red blood cells, some other types of white blood cells, and platelets.

[0095] Within these major categories, there are several subcategories including, but not limited to, acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-ALL, also called precursor B-lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and hairy cell leukemia (HCL). Thus, in certain embodiments, provided herein is a method of treating acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-ALL, also called precursor B-lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hairy cell leukemia (HCL) in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a composition described herein containing Compound 1. In some embodiments, the leukemia is relapsed or refractory leukemia. In some embodiments, the leukemia is relapsed or refractory acute lymphoblastic leukemia (ALL), relapsed or refractory precursor B-cell acute lymphoblastic leukemia (precursor B-ALL, also called precursor B-lymphoblastic leukemia), relapsed or refractory acute myeloid leukemia (AML), relapsed or refractory chronic myeloid leukemia (CML), or relapsed or refractory hairy cell leukemia (HCL).

[0096] Symptoms, diagnostic tests, and prognostic tests for each of the above-described conditions are known. See, for example, Harrison’s Principles of Internal Medicine, 16th ed., 2004, The McGraw-Hill Companies, Inc.; Dey et al. (2006), Cytojournal 3(24); and the “Revised European American Lymphoma” (REAL) classification system (see, e.g., the website maintained by the National Cancer Institute).

[0097] To establish the range of therapeutically effective doses of Compound 1 (or the formulations described herein containing Compound 1) for treating any of the above-mentioned diseases, several animal models are useful.

[0098] Compound 1 and its pharmaceutically acceptable salts "Compound 1" or "1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one" or "1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one" or "2-propen-1-one,1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl-" or ibrutinib or any other suitable name refers to a compound having the following structure.

Chemical formula

[0099] A variety of pharmaceutically acceptable salts are formed from Compound 1, including the following: - Acid addition salts formed by the reaction of Compound 1 with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc., for example acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.; - Acid addition salts formed by the reaction of Compound 1 with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.

[0100] The term "pharmaceutically acceptable salt" with reference to Compound 1 (ibrutinib) means a salt of Compound 1 that does not cause significant irritation to the mammal to which it is administered and does not substantially inhibit the biological activity and properties of the compound.

[0101] It should be understood that reference to pharmaceutically acceptable salts includes solvated forms (solvates). Solvates contain a solvent in either stoichiometric or non-stoichiometric amounts and are formed during the process of formation or isolation of the product using pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc. In one embodiment, the solvate is formed using, but not limited to, Class 3 solvents. The categories of solvents are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. In some embodiments, the solvate or pharmaceutically acceptable salt of Compound 1 (ibrutinib) is prepared or formed during the processes described herein for convenience. In some embodiments, the solvate of Compound 1 (ibrutinib) is anhydrous. In some embodiments, Compound 1 (ibrutinib) or its pharmaceutically acceptable salt exists in a non-solvated form. In some embodiments, Compound 1 (ibrutinib) or its pharmaceutically acceptable salt exists in a non-solvated form and is anhydrous.

[0102] In still other embodiments, compound 1 (ibrutinib) or a pharmaceutically acceptable salt thereof is prepared in various forms including, but not limited to, an amorphous phase, a crystalline form, a milled form, and a nanoparticle form. In some embodiments, compound 1 (ibrutinib) or a pharmaceutically acceptable salt thereof is amorphous. In some embodiments, compound 1 (ibrutinib) or a pharmaceutically acceptable salt thereof is amorphous and anhydrous. In some embodiments, compound 1 (ibrutinib) or a pharmaceutically acceptable salt thereof is crystalline. In some embodiments, compound 1 (ibrutinib) or a pharmaceutically acceptable salt thereof is crystalline and anhydrous.

[0103] In some embodiments, compound 1 (ibrutinib) is prepared as outlined in U.S. Patent No. 7,514,444.

[0104] Specific terms Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless otherwise stated. Further, the use of the terms "comprising" and other forms such as "include", "includes", and "included" is non-limiting.

[0105] The headings of the items used in this specification are for merely organizing purposes and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, papers, books, manuals, and treatises, are hereby expressly incorporated by reference in their entirety for all purposes.

[0106] When used before a numerical value, the term "about" indicates that the value can vary within a reasonable range, such as within ±10%, ±5%, or ±1% of the specified value.

[0107] As used herein, the term "comprising" is intended to mean that the compositions / formulations and methods, etc., include the recited elements but do not exclude others. When used to define compositions / formulations and methods, "consisting essentially of" means excluding other elements that have any essential significance for the intended use, but not excluding elements that do not substantially affect the characteristics of the composition / formulation or method. "Consisting of" means excluding elements not specifically recited. The embodiments defined by each of these transitional terms are within the scope of the present invention.

[0108] The terms "acceptable" or "pharmaceutically acceptable" with respect to a formulation, composition, or ingredient, as used herein, mean that they do not cause a continuous harmful effect on the overall health of the subject being treated, do not inhibit the biological activity or properties of the compound, and are relatively non-toxic.

[0109] As used herein, "amelioration" of the symptoms of a particular disease, disorder, or condition by administering a particular compound or pharmaceutical composition / formulation refers to any decrease in severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, continuous or transient, that may result from or be associated with the administration of the compound or composition / formulation.

[0110] "Bioavailability" refers to the percentage of the administered compound 1 that is delivered to the systemic circulation of the animal or human subject under study. The total exposure (AUC (0~∞) ) of the drug upon intravenous administration is typically defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which compound 1 is absorbed into the systemic circulation when a pharmaceutical formulation / composition is orally ingested as compared to intravenous injection. In one aspect of the present invention, the formulations / compositions described herein are contemplated to have suitable bioavailability.

[0111] "Plasma concentration" refers to the concentration of compound 1 in the plasma component of the subject's blood. It is understood that the plasma concentration of compound 1 can vary significantly among subjects due to variations associated with metabolism and / or possible interactions with other therapeutic agents. According to one embodiment disclosed herein, the plasma concentration of compound 1 can vary from subject to subject. Similarly, values such as the maximum plasma concentration (C max ), or the time to reach the maximum plasma concentration (T max ), or the total area under the plasma concentration-time curve (AUC (0~∞) ) can also vary from subject to subject. Due to this variability, the amount required to constitute a "therapeutically effective amount" of compound 1 or the formulations / compositions described herein containing compound 1 can vary from subject to subject. Furthermore, the formulations / compositions described herein can have a lower C max as described above, for example compared to a capsule formulation, due to the absorption process after administration. Preparing a suspension of ibrutinib having both pharmaceutically acceptable properties and desired PK properties such as a high C max , an equivalent C max or a sufficient C max is difficult.

[0112] As used herein, the term "Bruton's tyrosine kinase" refers to, for example, Bruton's tyrosine kinase derived from Homo sapiens as disclosed in U.S. Patent No. 6,326,469 (GenBank accession number NP_000052).

[0113] As used herein, the term "co-administration" and the like mean the administration of a selected therapeutic agent to a single patient, and are also intended to include treatment regimens in which the agent is administered by the same or different routes of administration or at the same or different times.

[0114] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of an agent or compound administered that is sufficient to moderate to some extent one or more of the symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, causes of the disease, or any other desired change in the biological system. For example, an "effective amount" for use in treatment is the amount of a formulation comprising a compound disclosed herein that is necessary to provide a clinically significant decrease in disease symptoms without accompanying excessive adverse side effects. The appropriate "effective amount" in any individual case can be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective to achieve the desired pharmacological effect or therapeutic improvement without accompanying excessive adverse side effects. It is understood that the "effective amount" or "therapeutically effective amount" can vary for each subject depending on variations in the metabolism of the compound, the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, a therapeutically effective amount can be determined by routine experimentation including, but not limited to, dose escalation clinical trials.

[0115] The term "inhibit", "inhibiting", or "inhibitor" of a kinase, as used herein, means the inhibition of the enzyme phosphotransferase activity.

[0116] As used herein, the term "irreversible inhibitor" means a compound that, upon contact with a target protein (e.g., a kinase), causes the formation of a new covalent bond with or within the protein, thereby reducing or abolishing one or more of the biological activities of the target protein (e.g., phosphotransferase activity), regardless of the subsequent presence or absence of the irreversible inhibitor.

[0117] As used herein, the term "prophylactically effective amount" refers to the amount of a formulation applied to a patient that alleviates to some extent one or more of the symptoms of a disease, condition or disorder being treated. In such prophylactic use, such amount may depend on the patient's health status, body weight, etc. It is considered well within the scope of those skilled in the art to determine such prophylactically effective amount by routine experimentation, including but not limited to dose escalation clinical trials.

[0118] As used herein, the terms "individual", "subject" or "patient" mean an animal that is the subject of treatment, observation or experiment. By way of example only, and not limitation, the subject can be a mammal, including but not limited to a human.

[0119] As used herein, IC 50 refers to the amount, concentration or dosage of a particular test compound that achieves 50% inhibition of the maximal response, such as inhibition of Btk, in an assay measuring a reaction.

[0120] As used herein, EC 50 refers to the dosage, concentration or amount of a particular test compound that causes a dose-dependent response at 50% of the maximal manifestation of a particular response induced, elicited or enhanced by the particular test compound.

[0121] Pharmaceutical composition / formulation As used herein, a pharmaceutical formulation (e.g., a suspension) refers to a mixture of Compound 1 and other chemical components (where applicable) described herein, such as carriers, diluents, suspending agents and / or excipients. The pharmaceutical formulation facilitates administration of the compound to a mammal. The compound can be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0122] An object of the present invention is to provide a formulation having appropriate in vivo utilization rate (e.g., an in vivo utilization rate advantageous as compared with a capsule approved by the FDA). Therefore, in one aspect, C maxThe GMR (geometric mean ratio) can be in the range of 75% to 95% (e.g., 80 to 85%), and the AUC last The GMR of last can be in the range of 85% to 110% (e.g., 85 to 100% or 85 to 95%), and / or the AUC inf (or the AUC ∞ ) The GMR can be in the range of 80% to 105% (e.g., 85 to 95%), and the formulations (e.g., suspensions) described herein are provided.

[0123] Such characteristics related to exposure can be part of any of the embodiments disclosed herein.

[0124] It should be understood that there is significant overlap between the additives used in the formulations described herein (e.g., between suspending agents and wetting agents). Thus, the additives (or components of the composition / formulation) referred to herein are to be regarded merely as illustrative examples of the types of additives that can be included in the compositions or formulations described herein, and are not to be construed as limiting. The amounts of such additives can be readily determined by those skilled in the art according to specific desired properties.

[0125] Administration and treatment regimen Since the following administration and treatment regimens refer to the amount of Compound 1, in the context of the present invention, the amounts can be appropriately extrapolated and applied to the amount of Compound 1 in the formulations (e.g., suspensions) described herein.

[0126] In some embodiments, the amount of Compound 1 administered to a mammal is 300 mg / day or more and 1000 mg / day or less. In some embodiments, the amount of Compound 1 administered to a mammal is 420 mg / day or more and 840 mg / day or less. In some embodiments, the amount of Compound 1 administered to a mammal is about 420 mg / day, about 560 mg / day, or about 840 mg / day. In some embodiments, the amount of Compound 1 administered to a mammal is about 420 mg / day. In some embodiments, the amount of Compound 1 administered to a mammal is about 560 mg / day. In some embodiments, the AUC of Compound 10~24 is from about 150 to about 3500 ng*h / ml. In some embodiments, the AUC of Compound 1 0~24 is from about 500 to about 1100 ng*h / ml. In some embodiments, Compound 1 is administered orally. In some embodiments, Compound 1 is administered once, twice, or three times a day. In some embodiments, Compound 1 is administered daily. In some embodiments, Compound 1 is administered once daily. In some embodiments, Compound 1 is administered every other day. In some embodiments, Compound 1 is maintenance therapy.

[0127] In some embodiments, the amount of Compound 1 administered to a pediatric population (e.g., humans up to 18 years old) is half of that described hereinabove. For example, each dose can be 30 - 140 mg, 50 - 100 mg, or 60 - 80 mg, such as about 70 mg (administered in 1 ml suspension form as described herein), and the daily dose for a pediatric population is from 150 mg / day to 500 mg / day. In some embodiments, the amount of Compound 1 administered to a pediatric population is from 210 mg / day to 420 mg / day. In some embodiments, the amount of Compound 1 administered to a pediatric population is about 210 mg / day, about 280 mg / day, or about 420 mg / day. In some embodiments, the amount of Compound 1 administered to a mammal is about 210 mg / day. In some embodiments, the amount of Compound 1 administered to a mammal is about 280 mg / day. In some embodiments, the AUC of Compound 1 0~24 is from about 150 to about 3500 ng*h / ml. In some embodiments, the AUC of Compound 1 0~24 is from about 500 to about 1100 ng*h / ml. In some embodiments, Compound 1 is administered orally. In some embodiments, Compound 1 is administered once, twice, or three times a day. In some embodiments, Compound 1 is administered daily. In some embodiments, Compound 1 is administered once daily. In some embodiments, Compound 1 is administered every other day. In some embodiments, Compound 1 is maintenance therapy.

[0128] The composition containing Compound 1 is administrable for prophylactic treatment, therapeutic treatment or maintenance treatment. In some embodiments, the composition containing Compound 1 is administered for therapeutic use (e.g., administered to a subject diagnosed with hematological malignancy). In some embodiments, the composition containing Compound 1 is administered for therapeutic use (e.g., administered to a subject who is susceptible to or otherwise at risk of developing hematological malignancy). In some embodiments, the composition containing Compound 1 is administered to a patient in remission as maintenance therapy.

[0129] In some embodiments, in the case of the pediatric population, the amount of Compound 1 is 150 mg / day or more and 500 mg / day or less. In some embodiments, the amount of Compound 1 is 210 mg / day or more and 420 mg / day or less. In some embodiments, the amount of Compound 1 is 200 mg / day or more and 420 mg / day or less. In some embodiments, the amount of Compound 1 is about 180 mg / day. In some embodiments, the amount of Compound 1 is about 210 mg / day. In some embodiments, the amount of Compound 1 is about 280 mg / day. In some embodiments, the amount of Compound 1 is about 420 mg / day. In some embodiments, in the case of the pediatric population, the amount of Compound 1 is 2 mg / kg / day or more and 13 mg / kg / day or less. In some embodiments, the amount of Compound 1 is 2.5 mg / kg / day or more and 8 mg / kg / day or less. In some embodiments, the amount of Compound 1 is 2.5 mg / kg / day or more and 6 mg / kg / day or less. In some embodiments, the amount of Compound 1 is 2.5 mg / kg / day or more and 4 mg / kg / day or less. In some embodiments, the amount of Compound 1 is about 2.5 mg / kg / day. In some embodiments, the amount of Compound 1 is about 8 mg / kg / day.

[0130] As described herein, the formulations of the present invention contain a pharmaceutical carrier such as purified water. Accordingly, the dosage is administered as a suspension of a certain volume. As described herein, when the dosage is 70 mg of ibrutinib, the amount of the carrier (e.g., purified water) is 1 ml. As indicated herein, the suspension can be of a lower concentration or a higher concentration, but in any case, the volume of the suspension required for a particular dosage is predetermined.

[0131] In some embodiments, the pharmaceutical formulations described herein contain about 70 mg of Compound 1. In some embodiments, the suspension is prepared such that the required dosage is available in a suspension of a predetermined volume (e.g., 1 ml) (obtainable via a syringe), and thus each 1 ml contains about 70 mg of Compound 1. In some embodiments, suspensions described herein of 1, 2, 3, 4 or 5 ml dosages are administered daily. In some embodiments, suspensions described herein of 2, 3 or 4 ml dosages are administered daily. In some embodiments, the dosage of the suspension described herein is administered once daily. In other embodiments, the dosage of the suspension described herein is administered multiple times a day.

[0132] In some embodiments, the formulations (e.g., suspensions) described herein are administered daily. In some embodiments, the formulations (e.g., suspensions) described herein are administered every other day.

[0133] In some embodiments, the formulations (e.g., suspensions) described herein are administered once a day. In some embodiments, the formulations (e.g., suspensions) described herein are administered twice a day. In some embodiments, the formulations (e.g., suspensions) described herein are administered three times a day. In some embodiments, the formulations (e.g., suspensions) described herein are administered four times a day.

[0134] In some embodiments, the formulations (e.g., suspensions) described herein are administered until the disease abhors it, the toxicity becomes unacceptable, or the individual selects to do so. In some embodiments, the formulations (e.g., suspensions) described herein are administered daily until the disease abhors it, the toxicity becomes unacceptable, or the individual selects to do so. In some embodiments, the formulations (e.g., suspensions) described herein are administered every other day until the disease abhors it, the toxicity becomes unacceptable, or the individual selects to do so.

[0135] The pharmaceutical compositions or formulations described herein can be in any suitable form for administering an exact dosage in a single administration (e.g., as a suspension using a measuring syringe or as a reconstitution powder containing a pre-prepared dosage in a sachet). Non-limiting examples are powders in vials or ampoules and aqueous suspension formulations / compositions packaged in single-dose non-resealable containers. Alternatively, multi-dose resealable containers can be used, in which case it is common to include a preservative in the formulation / composition. In some embodiments, each unit dosage form contains 70 mg of Compound 1 (and this can be 1 ml or another suitable predetermined volume of the suspension described herein). In some embodiments, an individual (e.g., a pediatric patient) is administered 1 unit dosage per day (e.g., as 1 ml of the suspension described herein, 70 mg of ibrutinib). In some embodiments, an individual (e.g., a pediatric patient) is administered 2 unit dosages per day (e.g., 2 × 1 ml of the suspension described herein, 140 mg of ibrutinib). In some embodiments, an individual (e.g., a pediatric patient) is administered 3 unit dosages per day (210 mg of ibrutinib). In some embodiments, an individual is administered 4 unit dosages per day (280 mg of ibrutinib).

[0136] Since the number of variables associated with individual treatment regimens is large and it is not uncommon for them to vary considerably from these recommended values, the above ranges are merely suggestions. Such dosages may be modified according to several variables including, but not limited to, the activity of the compound being used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0137] The toxicity and therapeutic efficacy of such treatment regimens can be determined in cell cultures or experimental animals by standard pharmaceutical procedures including, but not limited to, the determination of LD 50 (the dose lethal to 50% of the population) and ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio of LD 50 to ED 50 . Compounds with high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used to formulate dosage ranges for use in humans. The dosage of such compounds preferably lies within a range of circulating blood concentration that includes the ED 50 that minimizes toxicity. The dosage may vary within this range depending on the dosage form utilized and the route of administration utilized.

[0138] Combination therapy In certain embodiments, disclosed herein is a method of treating a blood cancer in an individual in need thereof, the method comprising administering to the individual a fixed amount of a formulation (e.g., a suspension) described herein that contains Compound 1. In some embodiments, the method further comprises administering a second blood cancer treatment regimen.

[0139] In some embodiments, the second cancer treatment regimen includes cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone and optionally rituximab.

[0140] In some embodiments, the second cancer treatment regimen includes bendamustine and rituximab.

[0141] In some embodiments, the second cancer treatment regimen comprises fludarabine, cyclophosphamide, and rituximab.

[0142] In some embodiments, the second cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone and optionally rituximab.

[0143] In some embodiments, the second cancer treatment regimen comprises etoposide, doxorubicin, vinblastine, cyclophosphamide, prednisone, and optionally rituximab.

[0144] In some embodiments, the second cancer treatment regimen comprises dexamethasone and lenalidomide.

[0145] Kit / Manufactured Article A kit or package containing the formulations described herein is designed for use in the methods described herein. The kit may further optionally contain one or more instruments such as instructions for handling for administering the formulation, a container suitable for the formulation, a syringe, a pipette, a measuring spoon, but not limited thereto. Other components for inclusion in the kit will be apparent to those skilled in the art considering the desired delivery instructions and mode.

[0146] For example, if the formulation is a suspension, it can be packaged in a bottle (e.g., a glass bottle) such as an amber glass bottle using a suitable adapter and / or sealing device. In one embodiment, such packaging further includes a metering device for oral administration of the suspension, which can be a pipette or a syringe. In one embodiment, the metering device is a pipette (e.g., having a tip) and a plunger (e.g., colored, neither translucent nor opaque but colored (e.g., can be blue and currently is purple, in accordance with the required regulations) to visually assist in the metering of the suspension). In one embodiment, the pipette or syringe is manufactured from a suitable polymer such as polypropylene, and furthermore, the plunger should also be manufactured from the same polymer as the pipette or, in one embodiment, from a specific polymer such as polyethylene (e.g., high-density polyethylene).

[0147] The kit typically includes a label listing the contents and / or instructions for use and a package insert with the instructions for use attached. A set of instructions will also typically be included.

[0148] In one embodiment, the label is present on or associated with the container. In one embodiment, if the letters, numbers, or other symbols forming the label are affixed, molded, or etched onto the container itself, the label is present on the container, and if it is present within a receptacle or carrier that also holds the container, the label is associated with the container (e.g., as a package insert). In one embodiment, the label is used to indicate that the contents are used for a specific therapeutic use. The label also indicates the usage of the contents, e.g., the usage of the method described herein.

Examples

[0149] The following examples are intended to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0150] Example 1 Examples of the formulations of the present invention can be described as follows.

[0151]

Table 1

[0152] Here, Avicel RC591 is used, which is a specific mixture of microcrystalline cellulose and croscarmellose sodium (sodium carboxymethylcellulose).

[0153] The details of the above formulations are based on the components in 1 ml of purified water. Thus, starting from 100 ml of purified water, the corresponding large-scale versions of the above formulations can be prepared (by multiplying the amounts of the components by 100).

[0154] Background Examples and Reference Examples Examples of various suspensions in which parabens are used as preservatives (e.g., sodium methylparaben and / or sodium ethylparaben) were tested and these were developed without problems to support clinical phase 1 studies (see the pamphlet of International Publication No. WO 2016 / 164404 of the international patent application). By modifying the phase 1 concept (mainly by increasing the percentage of parabens), a new multiple-dose concept was obtained for the purpose of supporting phase III clinical studies. These concepts are shown as Composition 1 and Composition 2 respectively in the following table.

[0155]

Table 2

[0156] Thus, for the above two suspensions, along with other changes such as an increase in the concentration of the suspending agents (microcrystalline cellulose and croscarmellose sodium) and a resulting increase in the amount of citric acid (due to the final target pH), the total amount of parabens increased by 20% (from Composition 1 to Composition 2).

[0157] As a result of the increase in parabens concentration, crystallization problems were observed in suspension composition 2 after several months in a stable state under various storage conditions. A large number of fine new needle crystals were observed under the microscope. IR, Raman and MS analyses characterized the new needle crystals as potentially a co-crystal of the API and parabens. As a unique result of this API-paraben co-crystallization, the amount of available parabens preservative resulted in poorer than expected results as established by the unexpectedly failing PET test reported in the table below (e.g., preservative effectiveness tests conducted and analyzed according to pharmacopeial references such as U.S. Pharmacopoeia <51> and Ph.Eur. 5.1.3).

[0158]

Table 3

[0159] In the last three entries (composition 2 and the same composition except that the pH was adjusted to 5.5 and 6.5), needle-shaped (co-)crystals were observed.

[0160] Thus, it can be seen that the composition / formulation with 120% parabens level failed the PET test.

[0161] The above formulations / compositions can be improved to achieve a more robust preservative system that covers the product shelf life. Further studies were conducted to provide alternative / improved suspensions that do not have drawbacks such as failing the PET test and / or formation of undesirable crystal (e.g., co-crystal) products (as outlined below). For example, it was desired / sought to achieve a more robust preservative system that covers the product shelf life and / or a suspension with a suitable particle size distribution throughout the suspension as described herein.

[0162] The above outlines the motivation to explore alternative forms of the suspension and to explore further preservatives for the suspension.

[0163] Study on the solubility of methyl, ethyl and propyl parabens at various temperatures at pH 6 (alone or in the presence of different amounts of propylene glycol) (In pure or in mixtures with various percentages of propylene glycol) The thermodynamic solubility of methyl, ethyl and propyl parabens was evaluated in buffer solution. Solubility was evaluated as a function of hypromellose concentration (0, 2.5 mg / ml, 5 mg / ml and 10 mg / ml) and as a function of temperature (5 °C, 20 °C and 40 °C). Saturated paraben solutions were spiked with an excess of the active ingredient (ibrutinib), filtered, and the ibrutinib / paraben concentration in the filtered solution was followed over time (1, 2, 3 and 4 weeks).

[0164] Results / Conclusions The addition of propylene glycol may have a slightly positive effect on the solubility of parabens. However, the paraben concentration in all formulations (and at all temperatures) decreased as a function of time after the addition of ibrutinib. This was accompanied by some physical observations such as the appearance of viscous substances in the vials, and additional peaks were observed in the chromatographic data in all samples at 40 °C.

[0165] Therefore, none of these various concepts were suitable for further development. In particular, methyl / ethyl parabens were not suitable.

[0166] Study of new concepts, methyl / ethyl parabens vs other preservatives To test the effect of the preservatives, 25 samples were prepared based on the following table. In each case, 70 mg / ml of ibrutinib was used, 1 mg / ml of sweetener (sucralose) was used, and the pH was adjusted using the adjusters mentioned herein.

[0167]

Table 4

[0168]

Table 5

[0169]

Table 6

[0170] To avoid any doubts, in the above table, Me Pa refers to methylparaben, Et Pa refers to ethylparaben, Pr Pa refers to propylparaben, and 1Q refers to 1H2O.

[0171] Thus, in combination with novel excipients or different processes, a completely novel preservative system using propylene glycol, ascorbic acid, benzoic acid or benzyl alcohol and parabens was tested. Avicel RC591 was compared with CL611, HPMC2910 5 mPas was compared with HPMC2208 3 mPas and HPC, the citrate / Na2HPO4 buffer was compared with the Na2HPO4 / NaH2PO4 buffer, and the use of parabens as Na salts (in a multi-step process) was compared with the use of non-ionic parabens (in a one-pot process).

[0172] Twenty-five novel concepts were screened in 6M laboratory stability studies and 1M ASAP (Accelerated Stability Assessment Program) stability studies in PET tests (storage conditions of 5, 40 and 60 °C).

[0173] Results of 25 samples The following general indicators were obtained from the results of the 1-month (1M) ASAP (Accelerated Stability Assessment Program) stability study (storage conditions of 5 °C, 40 °C and 60 °C).

[0174] - The results of API assay, purity profile, pH and suspension appearance in all cases were stable and good.

[0175] - Only in terms of preservative stability, some important differences were observed among different concepts. For parabens, a 1 - 6% reduction was observed in the assay of samples stored at 60°C for 1 month (1M). The sorbic acid assay showed a reduction of about 15%, benzoic acid about 5%, and benzyl alcohol only 1%.

[0176] Results of 6 - month (6M) laboratory stability Twenty - five new concepts were mainly screened for physical stability under various stress conditions: viscosity, yield point, visual aspects, and API (co) - crystallization (at various time points).

[0177] The viscosity and yield point of all suspensions over time were acceptable. Only the Avicel structure of the sample containing benzoic acid at pH 4 after 6 months (6M) completely broke down without a yield point. Avicel is expected to be more stable at 5 < pH < 9.

[0178] The investigation of the visual aspects of the suspensions (powder precipitation, water separation, structure breakdown, etc.) was carried out by observing the samples stored statically in a glass cylinder for 6M. As a conclusion, in all concepts, the suspensions in the cylinder resulted in a high - density form that could not flow even when the cylinder was inverted for 10 seconds. Neither powder precipitation nor water separation was observed. The only exception was represented by the concept containing Avicel combined with HPC (Concept 4), which showed about 2.5 ml of water separation at the bottom of the cylinder.

[0179] The investigation of possible new needle - like crystals (typical of co - crystal API - parabens) was carried out by microscopic analysis of suspension samples stored / handled in various ways.

[0180] - All concepts were stored at 40 and 60°C for 1M: new crystals were discovered only in Concepts 22 and 24.

[0181] - All concepts were stored over 6M under cyclic conditions (5°C / 12h to 40°C / 12h): After 1M, no new needle crystals appeared in only 7 concepts (13 - 20), which were observed in all other samples. For acceptable concepts 13 - 20, after 6M storage under cyclic conditions, new crystallization was observed only in concepts containing benzoic acid as an incipient. The other samples were stable.

[0182] - All concepts were subjected to physical stress by rolling. All suspension concepts were rolled horizontally at room temperature in glass vials closed with pediatric safety stoppers at a speed of 25 rpm over 1M. No co-crystals were found after 1M of rolling, and overstress was applied by rolling a total of 3 months under the same conditions to promising concepts 9, 17, 18, 19, and 20 in which no other problems were found in other tests, followed by standing at room temperature for 3 months (3M). Among these concepts, only concepts 18, 19, and 20 were stable. New crystals were observed in concept 9, and possible initial crystallization was observed in concept 17.

[0183] - Spiking of samples with co-crystals. Some concepts were spiked to attempt to induce rapid co-crystallization. Concepts containing methyl and ethyl parabens were spiked with a few granules of the powder of the co-crystals of API / methyl paraben and API / Et paraben. After spiking, the samples were homogenized by shaking (by hand), evaluated under a microscope (some crystals had already been observed before spiking in samples 24 and 25), and finally stored for 6M under cyclic conditions. As a conclusion, after storage for 1M to 6M under cyclic conditions, all samples showed new needle crystals.

[0184] PET results and analysis (for concepts 17 - 20) PET tests were performed on all concepts, and the results of the most promising concepts (see above) are shown below.

[0185]

Table 7

[0186] Based on the results obtained from 25 screened concepts (mainly PET results and the formation of new needle (co)crystals in one or more of the test conditions), the first concept selection was made when 2M stability data was available. Only concepts 17 and 18 (containing benzoic acid and benzyl alcohol respectively as new preservatives) were selected for further investigation (see the table below).

[0187]

Table 8

[0188] Additional data on the concepts of benzyl alcohol and benzoic acid To test the stability and the effect of the preservatives, based on the following table, 13 more samples (concepts 26 - 38) were prepared using benzoic acid and benzyl alcohol, with 70 mg / ml of ibrutinib as the free base and 1 mg / ml of the sweetener (sucralose) in each case, and the pH was adjusted using the adjusters mentioned herein.

[0189]

Table 9

[0190]

Table 10

[0191] In the PET test and 2M laboratory stability study, the concentrations of the suspension preservatives benzyl alcohol and benzoic acid were screened at target and limiting pHs in combination with various Avicel concentrations (12 and 14 mg / ml) and different wetting agents (HPMC2910 and HPMC2208) (see above for the method).

[0192] PET results for concepts 26 - 38 The results of the PET tests conducted on the newly screened concepts are reported in the following table, where it can be seen that all concepts passed.

[0193]

Table 11

[0194]

Table 12

[0195]

Table 13

[0196]

Table 14

[0197] Conclusions from Concepts 26 - 38 Some suspension concepts containing benzoic acid were physically unstable. After 2 months of observation at the lower pH and 6 months of observation at the target pH, the Avicel structure completely disappeared (yield point was not measured). This result was probably associated with a very low application pH that is necessary for the antibacterial activity of benzoic acid but causes the instability of Avicel. Avicel is expected to be more stable within the range of 5 < pH < 9.

[0198] In combination with the benzoic acid concept, some new crystallization was observed after storage at 6M under cyclic conditions and after 3M of rolling and 3M of static storage.

[0199] These preliminary results showing a possible co - crystallization of ibrutinib and benzoic acid are also confirmed by the disclosures of International Patent Application Publication No. WO 2016 / 156127 and WO 2016 / 160604.

[0200] The concept of containing benzyl alcohol as a preservative was physically / chemically stable and showed no (co)crystallization.

[0201] In conclusion, based on these results, benzoic acid was not further evaluated, while benzyl alcohol was selected as a potential new suspension preservative and for further development research.

[0202] From the PET results, the target amount of benzyl alcohol was preliminarily selected as 10 mg / ml: the first positive result was obtained at 8 mg / ml, and an additional 20% of benzyl alcohol was taken into consideration for reasons of process robustness.

[0203] Concept using benzyl alcohol Wetting agent The need for a wetting agent such as HPMC was tested: the physical stability and particle size distribution (PSD) of the suspension were tested, and the absence of HPMC was found to result in a physically unstable suspension after storage at 25°C for 1 month and a shift to larger particle sizes (PS) after storage at 25°C for 2 months. Therefore, the formulations / suspensions of the present invention without HPMC (or another suitable wetting agent) are not recommended. Without a wetting agent, it is conceivable that the particle size may (undesirably) increase due to agglomeration.

[0204] HPMC 2910 and 2208 were compared with respect to hydrophobicity, water solubility, proportion of free OH, and surface tension, and the following results were obtained.

[0205] HPMC is a thermoreversible polymer with a specific clouding / gelation temperature associated with polymer agglomeration upon increasing temperature. The clouding / gelation temperature is a function of polymer concentration, length of the hydrophobic block, and chemical structure of the polymer. The more hydrophobic the polymer, the lower the clouding / gelation temperature. HPMC 2208 is less hydrophobic than 2910, and the resulting clouding temperature is approximately 20°C higher than the clouding temperature of HPMC 2910.

[0206] HPMC2208 is less hydrophobic and more water-soluble than HPMC2910. This is expected to result in it being more readily utilizable as a wetting agent for the API (ibrutinib).

[0207] The surface tension of the HPMC2208 aqueous solution is higher than that of the HPMC2910 aqueous solution at the same concentration. HPMC2208 is expected to be a better wetting agent for the API.

[0208] From the NMR tests, it was observed that 3 mPas HPMC2208 contains approximately 18% more free OH groups than HPMC2910, along with the other results found.

[0209] Conclusion: Therefore, in one embodiment, 3 mPas HPMC2208 was selected as a new wetting agent for the ibrutinib suspension because it is expected to be a better wetting agent mainly based on the above.

[0210] Other tests By titration, the amount of citric acid.H2O to obtain the target suspension pH = 6.00 ± 0.1 was determined to be 0.7302 mg / ml.

[0211] · The suspension buffer volume quantification was moderate / good, and the determination of the suspension concentration was 1.021 g / ml.

[0212] · The robustness study of PET showed positive results.

[0213] · The DoE sensitivity study conducted on the suspension to evaluate the API / benzyl alcohol / degradant assay and the sensitivity of the pH to temperature, oxygen, light, and steel quality characteristics showed positive results.

[0214] · The DoE robustness study was conducted on the suspension to evaluate the manufacturing variations (90 - 110 w%) of the excipients and positive results (in progress) were obtained.

[0215] ·Performed the study on the robustness of the pH boundary not suitable, for the concepts selected at the pH boundaries (5.5 and 6.5), and obtained positive results (in progress).

[0216] Scale-up of the process Example - Pharmaceutical formulation / Preparation process The pharmaceutical formulation / composition of the present invention (the above suspension) can be prepared or manufactured by mixing appropriate components with each other. Examples of this process include: ·Preparing the crystalline form A of ibrutinib described in this specification (for example, referring to the pamphlet of International Publication No. 2013 / 184572); ·Mixing the remaining components with each other.

[0217] Large-scale preparation Manufacturing process at a 50 L scale as follows ·Adding purified water to blending container 1 ·Adding a solution of HPMC and benzyl alcohol dissolved in purified water ·Adding the API and stirring the preparation mixture in container 1 until homogeneous ·Adding Avicel to preparation container 1 ·Adding a solution of sucralose, Na2HPO4 and citric acid H2O in purified water to container 1 ·Stirring the preparation mixture until homogeneous ·Measuring the pH of the preparation ·Adjusting the preparation mixture to the final volume by adding purified water ·Mixing the preparation mixture until homogeneous ·Measuring the final pH.

[0218] The above process can be adapted / modified according to the components included in the pharmaceutical formulation / composition (for example, based on the specific suspending agent, wetting agent, etc. used).

[0219] Biological example A study is conducted to test the safety, tolerability, and / or efficacy of the formulations of the present invention (particularly formulations that are suspensions) in subjects having a disease defined herein (such as chronic lymphocytic leukemia, relapsed / refractory mantle cell lymphoma, etc.) (e.g., in a pediatric population). Similar studies can also be carried out to test such formulations in combination (as described herein). The present invention includes the following embodiments. [Claim 1] (i) Ibrutinib or a pharmaceutically acceptable salt / solvate thereof, which is a compound having the structure of Compound 1

Chemical formula

Chemical formula

Claims

1. (i) Ibrutinib, which is a compound having the structure of Compound 1 【Chemical Formula 1】 or a pharmaceutically acceptable salt / solvate thereof, and a suspending agent, and (ii) one or more preservatives, wherein at least one preservative is benzyl alcohol, and optionally, one or more other pharmaceutically acceptable excipients A stable pharmaceutical formulation comprising the pharmaceutical formulation contains from about 0.1 w / v% to 10 w / v% or from about 1 mg / ml to 50 mg / ml of preservative, the preservative contains more than 90% benzyl alcohol by weight, a pharmaceutical formulation.

2. The pharmaceutical formulation according to claim 1, wherein the (i) ibrutinib or a pharmaceutically acceptable salt / solvate thereof, and the suspending agent are in the presence of a pharmaceutically acceptable carrier.

3. (i) Compound 1 suspended in a pharmaceutically acceptable carrier 【Chemical Formula 2】 Ibrutinib, which is a compound having the structure of or a pharmaceutically acceptable salt / solvate thereof, and (ii) at least one preservative which is benzyl alcohol, and optionally, one or more other pharmaceutically acceptable excipients The pharmaceutical formulation according to claim 1 or 2, which is in the form of a suspension comprising

4. The pharmaceutical formulation according to any one of claims 1 to 3, further containing a preservative selected from one or more of an antibacterial agent, an antioxidant, a free radical scavenger, an oxygen scavenger and / or a chelating agent.

5. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the preservative consists essentially of benzyl alcohol.

6. The pharmaceutical formulation according to claim 5, wherein the preservative is about 0.5 w / v% to 2 w / v% or about 5 mg / ml to 20 mg / ml.

7. The pharmaceutical formulation according to any one of claims 1 to 6, comprising a suspending agent selected from alginate, cellulose ether, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, acacia, tragacanth, xanthan gum, bentonite, carbomer, carrageenan, powdered cellulose and gelatin.

8. The pharmaceutical formulation according to claim 7, wherein the suspending agent comprises microcrystalline cellulose.

9. The pharmaceutical formulation according to any one of claims 1 to 8, containing the suspending agent in an amount of 0.1 w / v% to 10 w / v% or about 1 mg / ml to 50 mg / ml.

10. The pharmaceutical formulation according to claim 9, wherein the amount of the suspending agent is about 0.5 w / v% to 2 w / v% or about 5 mg / ml to 20 mg / ml.

11. The pharmaceutical formulation according to any one of claims 1 to 10, further comprising one or more wetting agents, one or more buffering agents, one or more pH adjusting agents and / or optionally a sweetening agent.

12. Based on 1 ml of the pharmaceutical carrier being purified water, 20 to 200 mg / ml of ibrutinib; 2.5 to 25 mg / ml of benzyl alcohol preservative; 2 to 24 mg / ml of suspending agent; optionally 0.5 to 10 mg / ml of wetting agent; optionally 0.5 to 10 mg / ml of buffer solution; optionally 0.1 to 5 mg / ml of sweetening agent; and optionally a pH adjusting agent (q.s.), the pharmaceutical formulation according to any one of claims 1 to 11.

13. The pharmaceutical formulation according to claim 12, comprising 60 to 80 mg / ml of ibrutinib, 8 to 12 mg / ml of benzyl alcohol preservative, 10 to 14 mg / ml of suspending agent, optionally 2 to 3 mg / ml of wetting agent, optionally 1.5 to 2.5 mg / ml of buffer, optionally 0.5 to 1.5 mg / ml of sweetening agent, and optionally pH adjuster (q.s.), based on the pharmaceutical carrier which is 1 ml of purified water.

14. The pharmaceutical formulation according to any one of claims 1 to 11, comprising the following relative amounts (w / w) with respect to 70 mg of ibrutinib: 5 to 15 mg of benzyl alcohol preservative, 6 to 18 mg of suspending agent, optionally 1 to 5 mg of wetting agent, optionally 1 to 3 mg of buffer, optionally 0.2 to 2 mg of sweetening agent, and optionally pH adjuster (q.s.).

15. 8 to 12 mg of benzyl alcohol preservative, 10 to 14 mg of a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, optionally 2 to 3 mg of hydroxypropyl methylcellulose (HPMC), optionally 1.5 to 2.5 mg of citric acid.H ２ O and / or phosphate such as sodium hydrogen phosphate, optionally 0.5 to 1.5 mg of sucralose, and optionally NaOH and / or HCl (q.s.) for adjusting the pH, the pharmaceutical formulation according to claim 14.

16. The pharmaceutical formulation according to any one of claims 1 to 15, wherein the ibrutinib is not in the form of a salt or solvate, that is, the ibrutinib is in its free form.

17. The pharmaceutical formulation according to any one of claims 1 to 16, which is used in the treatment of diseases.

18. The pharmaceutical formulation according to any one of claims 1 to 16, which is used in a method for treating B-cell proliferative diseases.

19. The pharmaceutical composition according to claim 18, wherein the B cell proliferative disorder is diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.

20. The pharmaceutical composition according to claim 17, wherein the disease is a B cell malignancy.

21. The pharmaceutical composition according to claim 20, wherein the disease is a B cell malignancy selected from chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and multiple myeloma.

22. The pharmaceutical composition according to claim 21, wherein the disease is lymphoma or leukemia.

23. The pharmaceutical composition according to claim 21, wherein the disease is diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia or lymphomatoid granulomatosis.

24. The pharmaceutical composition according to claim 2 or 3, wherein the pharmaceutically acceptable carrier is an aqueous carrier or purified water.

25. The pharmaceutical composition according to any one of claims 2, 3 and 24, wherein the pharmaceutically acceptable carrier is present in an amount of 1 ml per 10 mg of ibrutinib to 1 ml per 210 mg of ibrutinib, or in an amount of about 1 ml per 70 mg of ibrutinib.

26. A pharmaceutical formulation according to any one of claims 1 to 25, comprising a preservative selected from the group consisting of benzoic acid, parabens (methyl or ethyl paraben), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorobutanol, gallate, hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-γ-picolinium chloride, phenylmercuric acetate, thimerosal, sorbic acid, propionic acid, propylene glycol, vitamin E, ascorbyl palmitate, sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine, methionine, thioglycerol, sodium acetone bisulfite, isoascorbic acid, hydroxypropyl cyclodextrin, sodium citrate, sodium EDTA, malic acid, acetic acid and mixtures thereof.

27. The pharmaceutical formulation according to claim 8, wherein the microcrystalline cellulose is silicified microcrystalline cellulose SMCC.

28. The wetting agent comprises a cellulose ether selected from hydroxypropyl cellulose or hydroxypropyl methyl cellulose, The buffer comprises citric acid. H ２ O and / or sodium hydrogen phosphate, The pH adjuster comprises sodium hydroxide and / or hydrochloric acid, The pharmaceutical formulation according to claim 11, wherein the sweetening agent comprises sucralose.

29. The pharmaceutical formulation according to claim 15, wherein the mixture of the microcrystalline cellulose and sodium carboxymethyl cellulose is Avicel (registered trademark).

30. A process for preparing a pharmaceutical formulation according to any one of claims 1 to 29, the process comprising mixing the components of the pharmaceutical formulation with each other.

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