Acalabrutinib maleate dosage form

Abstract

The present disclosure generally relates to (a) solid pharmaceutical dosage forms comprising acalabrutinib maleate; (b) methods of using such pharmaceutical dosage forms to treat B-cell malignancies and / or other conditions; (c) kits comprising such pharmaceutical dosage forms and, optionally, a second pharmaceutical dosage form comprising another therapeutic agent; (d) methods for preparing such pharmaceutical dosage forms; and (e) pharmaceutical dosage forms prepared by such methods.

Description

[Technical Field]

[0001] The present disclosure generally relates to (a) solid pharmaceutical dosage forms comprising acalabrutinib maleate; (b) methods of using such pharmaceutical dosage forms to treat B-cell malignancies and / or other conditions; (c) kits comprising such pharmaceutical dosage forms and, optionally, a second pharmaceutical dosage form comprising another therapeutic agent; (d) methods for preparing such pharmaceutical dosage forms; and (e) pharmaceutical dosage forms prepared by such methods. [Background technology]

[0002] Acalabrutinib is a selective, covalent inhibitor of Bruton's tyrosine kinase ("BTK"). It is the active pharmaceutical ingredient in CALQUENCE®, a formulation approved in several countries (including the United States, Canada, and Australia) for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and mantle cell lymphoma. CALQUENCE® is sold as a capsule dosage form containing 100 mg of crystalline acalabrutinib free base (specifically, anhydrous Form A). Patent Document 1 reports anhydrous Form A, additional crystalline acalabrutinib free base forms, and crystalline acalabrutinib salt forms (including, for example, citrate, fumarate, gentisate, maleate, oxalate, phosphate, sulfate, and L-tartrate salts of acalabrutinib). The prescribing information for CALQUENCE® recommends avoiding co-administration with gastric acid-reducing agents due to the potential for decreasing the plasma concentrations of acalabrutinib. Thus, there is a need for a pharmaceutical dosage form of acalabrutinib that reduces the potential effect of gastric acid-reducing agents on the plasma concentrations of acalabrutinib when co-administered with acalabrutinib dosage forms. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2017 / 002095 Brochure Summary of the Invention [Means for solving the problem]

[0004] In one aspect, the disclosure provides a solid pharmaceutical dosage form for oral administration to a human comprising about 75 mg to about 125 mg (free base equivalent) of acalabrutinib maleate and at least one pharmaceutically acceptable excipient, wherein the dosage form comprises: conditions in which at least about 75% of acalabrutinib maleate dissolves within about 30 minutes as measured in an in vitro dissolution test conducted using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and The present invention relates to a solid pharmaceutical dosage form that satisfies the conditions that at least about 75% of acalabrutinib maleate dissolves within about 60 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a 900 mL dissolution volume, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle speed of 75 RPM. In a further embodiment, the solid pharmaceutical dosage form comprises about 75 mg to about 100 mg (free base equivalent) of acalabrutinib maleate. In yet a further embodiment, the acalabrutinib maleate is present as acalabrutinib maleate monohydrate, such as crystalline acalabrutinib maleate monohydrate Form A.

[0005] In another aspect, the present disclosure relates to a solid pharmaceutical dosage form as described above, wherein the dissolution rate of acalabrutinib maleate in a 5 mM phosphate pH 6.8 dissolution medium does not decrease by more than 20% from its initial dissolution rate after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months.

[0006] In another aspect, the disclosure relates to one or more solid pharmaceutical dosage forms as described above, wherein no more than about 5% (w / w) of the acalabrutinib maleate present in the dosage form is degraded after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months.

[0007] In another aspect, the disclosure provides a dosage form that is bioequivalent to a 100 mg Calquence® capsule when orally administered to fasted human subjects not receiving a gastric acid reducing agent, wherein the relative mean C of the dosage form to the 100 mg Calquence® capsule is: max , AUC (0-t) , and AUC (0-∞) The present invention relates to one or more of the solid pharmaceutical dosage forms described above that are bioequivalent when the confidence interval of the above is within the range of 80% to 125%.

[0008] In another aspect, the disclosure provides a dosage form that, when administered twice daily to a population of fasted human subjects, Mean C for a population of human subjects max a value of about 400 ng / mL to about 900 ng / mL; Mean AUC for a population of human subjects (0-24) a value of about 350 ng·hr / mL to about 1900 ng·hr / mL; and / or Mean AUC for a population of human subjects (0-∞) The present invention relates to one or more solid pharmaceutical dosage forms described above that satisfy one or more of the pharmacokinetic conditions of acalabrutinib, wherein the pharmacokinetic value is from about 350 ng·hr / mL to about 1900 ng·hr / mL.

[0009] In another aspect, the present disclosure relates to one or more of the solid pharmaceutical dosage forms described above, wherein the dosage form provides a median steady-state Bruton's tyrosine kinase occupancy in peripheral blood mononuclear cells of at least about 90% when administered twice daily to a human subject.

[0010] In another aspect, the present disclosure provides a dosage form comprising: acalabrutinib maleate in an amount of about 15% to about 55% by weight of the dosage form; at least one diluent in an amount of about 10% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 0.5% to about 15% by weight of the dosage form; and at least one lubricant in an amount of about 0.25% to about 4% by weight of the dosage form; The present invention relates to one or more of the solid pharmaceutical dosage forms described above, wherein the sum of the individual amounts equals 100% of the total weight of the dosage form.

[0011] In another aspect, the present disclosure provides a dosage form comprising: Acalabrutinib maleate monohydrate in an amount of about 30% to about 35% (free base equivalent) by weight of the dosage form; Mannitol in an amount of about 30% to about 35% by weight of the dosage form; microcrystalline cellulose in an amount of about 25% to about 30% by weight of the dosage form; hydroxypropyl cellulose in an amount of about 3% to about 7% by weight of the dosage form; and sodium stearyl fumarate in an amount of about 1% to about 4% by weight of the dosage form; The present invention relates to one or more of the solid pharmaceutical dosage forms described above, wherein the sum of the individual amounts equals 100% of the total weight of the dosage form. [Brief explanation of the drawings]

[0012] [Figure 1] 1 is a representative XRPD diffractogram of crystalline acalabrutinib maleate monohydrate Form A. [Figure 2] Figure 1 shows the dissolution profiles of phosphate, oxalate, and maleate salts of acalabrutinib in simulated gastric acid / FaSSIF-V2 medium. [Figure 3] Figure 1 shows the elution profiles of phosphate, oxalate, and maleate salts of acalabrutinib in deionized water / FaSSIF-V2 medium. [Figure 4] 1 is a dynamic water vapor sorption plot of acalabrutinib phosphate. [Figure 5] 1 is a thermogravimetric analysis plot of acalabrutinib phosphate. [Figure 6]1 is an XRPD diffractogram of acalabrutinib phosphate. [Figure 7] 1 is a thermogravimetric analysis plot of acalabrutinib oxalate. [Figure 8] 1 is a dynamic water vapor sorption plot of acalabrutinib oxalate. [Figure 9A] 1 is a thermogravimetric analysis plot of acalabrutinib maleate. [Figure 9B] 1 is a thermogravimetric analysis plot of acalabrutinib maleate carried out under an alternative set of conditions. [Figure 10A] 1 is a dynamic vapor sorption plot of a first sample of acalabrutinib maleate. [Figure 10B] 1 is a dynamic vapor sorption plot of a second, higher quality sample of acalabrutinib maleate. [Figure 11] Figure 1 shows the dissolution profiles of micronized and unmilled acalabrutinib maleate in simulated gastric acid / FaSSIF-V2 medium. [Figure 12] Figure 1 shows the dissolution profiles of micronized and unmilled acalabrutinib maleate in deionized water / FaSSIF-V2 media. [Figure 13] Figure 1 shows the solubility of acalabrutinib maleate and acalabrutinib free base in various buffer solutions versus final pH values. [Figure 14] Figure 1 shows dissolution profiles obtained from low pH studies under sink conditions for acalabrutinib maleate tablets T16, T17, and T18, and acalabrutinib free base capsules C1. [Figure 15] Figure 1 shows the dissolution profiles obtained from low ionic strength testing at neutral pH under sink conditions for acalabrutinib maleate tablets T16, T17, and T18. [Figure 16] Figure 1 shows the dissolution profiles obtained from high ionic strength testing at neutral pH for acalabrutinib maleate tablets T13 and acalabrutinib free base capsules C2. [Figure 17]Figure 1 shows the dissolution profiles obtained in unbuffered neutral medium (i.e., conditions similar to a proton pump inhibitor-treated stomach) for acalabrutinib maleate tablets T1 and acalabrutinib free base capsules C1. [Figure 18] Figure 1 shows the dissolution profiles obtained from unbuffered neutral medium for acalabrutinib maleate tablets T13 and acalabrutinib free base capsules C1. [Figure 19] Figure 1 shows the dissolution profile of acalabrutinib maleate tablet T19 under pH shift conditions. [Figure 20] Figure 1 shows the dissolution profiles of acalabrutinib maleate tablets T19 and acalabrutinib free base capsules C3 under pH shift conditions. [Figure 21] Figure 10 is a plot of the % effective cumulative amount of acalabrutinib versus time (minutes) for acalabrutinib maleate tablets T19 and acalabrutinib free base capsules C2 when assessed in the TIM-1 system under gastric conditions associated with an acidic gastric compartment and also under gastric conditions associated with concomitant administration of a proton pump inhibitor or acid reducing agent. [Figure 22] Figure 1 shows the particle size distribution of acalabrutinib maleate tablets T10 (D(v,0.9) ≒ 150 μm), T11 (D(v,0.9) ≒ 16 μm), T13 (D(v,0.9) ≒ 500 μm), and T15 (D(v,0.9) ≒ 70 μm). [Figure 23] Figure 1 shows the dissolution profiles of acalabrutinib maleate tablets T10, T11, T13, and T15 (26% drug load by weight) in 5 mM sodium phosphate buffer medium. [Figure 24] Figure 1 shows the dissolution profiles of acalabrutinib maleate tablets T9, T2, and T14 (43% drug load by weight) in 5 mM sodium phosphate buffer medium. [Figure 25] Report on the results of an in vivo study in a dog model measuring the AUC(0-24) values ​​of acalabrutinib free base and acalabrutinib maleate when co-administered with omeprazole. [Figure 26]Figure 1 shows the dissolution profiles of several binary mixtures of disintegrant and acalabrutinib maleate (1:5 ratio) in deionized water medium. [Figure 27] Figure 1 shows the dissolution profiles of several binary mixtures of lubricant and acalabrutinib maleate (1:15) in deionized water medium. [Figure 28] Figure 1 shows the dissolution profiles of tablet cores T2 and T3 in deionized water medium. [Figure 29] Figure 1 shows the dissolution profiles of tablet cores T6 and T8 in deionized water medium. [Figure 30] Figure 1 shows the dissolution profiles of tablet cores T4 and T5 in deionized water medium. [Figure 31] 1 shows a schematic overview of the process for preparing acalabrutinib maleate tablet T21 of Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0013] I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0014] When ranges are used, for example to describe quantities, all combinations and subcombinations and specific embodiments of ranges are intended to be included.

[0015] The singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0016] The use of the term "about" when referring to a number or numerical range means that the referenced number or numerical range is an approximation within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary. The variation is typically 0% to 15%, preferably 0% to 10%, and more preferably 0% to 5% of the stated number or numerical range. In many cases, the term "about" may include numbers that are rounded to the nearest significant figure.

[0017] The term "acalabrutinib" refers to the International Nonproprietary Name (INN) of the compound 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide, which has the chemical structure shown below. [ka] WO 2013 / 010868 discloses acalabrutinib (Example 6) and describes the synthesis of acalabrutinib. WO 2020 / 043787 further describes the synthesis of acalabrutinib. WO 2013 / 010868 and WO 2020 / 043787 are each incorporated by reference in their entirety.

[0018] The term "acalabrutinib maleate monohydrate" refers to crystalline acalabrutinib maleate monohydrate, including acalabrutinib maleate monohydrate crystalline form A. Example 6.2 of WO 2017 / 002095 describes the preparation of acalabrutinib maleate monohydrate crystalline form A. WO 2017 / 002095 is incorporated by reference in its entirety. Acalabrutinib maleate monohydrate form A may also be referred to by the alternative nomenclature acalabrutinib maleate monohydrate form 1. Unless otherwise specified, all references in this disclosure to amounts of acalabrutinib, acalabrutinib maleate, or acalabrutinib maleate monohydrate are based on acalabrutinib free base equivalents. For example, 100 mg refers to 100 mg of acalabrutinib free base, or the equivalent amount of acalabrutinib maleate or acalabrutinib maleate monohydrate.

[0019] The term "ACP-5862" refers to the compound 4-[8-amino-3-[4-(but-2-ynoylamino)butanoyl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide, having the chemical structure shown below. [ka] ACP-5862 is the active metabolite of acalabrutinib.

[0020] "AUC (0-24) The term "area under the plasma concentration-time curve from time 0 (time of administration) to 24 hours post-dose as calculated by the linear trapezoidal method.

[0021] "AUC (0-∞) The term "area under the plasma concentration-time curve from time 0 (time of administration) to infinity (∞) as calculated by the linear trapezoidal method.

[0022] The term "BID" means twice in die, twice a day, or twice daily.

[0023] "C max The term "" refers to the peak plasma concentration over the entire sampling period.

[0024] The terms "co-administration," "in combination with," and "combination" can refer to the administration of two or more therapeutic agents. In one aspect, "combination" can refer to simultaneous administration (e.g., administering both agents substantially simultaneously, albeit in separate dosage forms). In a further aspect of the invention, "combination" can refer to sequential administration (e.g., administering a first agent followed by a delay, followed by administration of a second or additional agent). When administration is sequential, the delay in administering the latter component should not be too long or too short, so as not to eliminate the benefit of the combination.

[0025] Unless the context otherwise requires, the words "comprise," "comprises," and "comprising" are used with the express understanding that they are to be interpreted inclusively, not exclusively, and that applicant intends each of those words to be so interpreted in interpreting this patent, including the claims that follow.

[0026] The term "crystalline", when applied to acalabrutinib, acalabrutinib maleate, or acalabrutinib maleate monohydrate, refers to the solid-state form in which the molecules are arranged to form a distinct crystal lattice that (i) contains a distinct unit cell and (ii) gives rise to a distinct diffraction peak when exposed to X-rays.

[0027] The term "crystalline purity" refers to the crystalline purity of acalabrutinib, acalabrutinib maleate, or acalabrutinib maleate monohydrate for a particular crystalline form as determined by X-ray powder diffraction analysis.

[0028] The term "crystallization" as used throughout this application may refer to crystallization and / or recrystallization as applicable to the preparation of acalabrutinib, acalabrutinib maleate, or acalabrutinib maleate monohydrate.

[0029] As used throughout this application, (0.1) " and "D (v,0.1) The term "particle size" means that 10% of the total volume of material in a sample has a particle size below a particular value as measured by laser diffraction.

[0030] As used throughout this application, (0.5) " and "D (v,0.5) The term "particle size" means that 50% of the total volume of material in a sample has a particle size below a particular value as measured by laser diffraction.

[0031] As used throughout this application, (0.9) " and "D (v,0.9) The term "particle size" means that 90% of the total volume of material in a sample has a particle size below a particular value as measured by laser diffraction.

[0032] The term "pharmaceutically acceptable" (as in "pharmaceutically acceptable diluent" or "pharmaceutically acceptable disintegrant") refers to a material that is suitable for administration to a subject, e.g., a material that does not cause undesired biological effects. Examples of pharmaceutically acceptable excipients are described in "Handbook of Pharmaceutical Excipients," Rowe et al., Ed. (Pharmaceutical Press, 7th Ed., 2012).

[0033] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inactive ingredients. Any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is contemplated for use in the therapeutic compositions of the invention except insofar as it is incompatible with acalabrutinib, acalabrutinib maleate, or acalabrutinib maleate monohydrate.

[0034] The term "Q" refers to the amount of active substance in a sample (Q) that dissolves at a specific time and is expressed as a percentage of the total amount of active substance present in the sample.

[0035] The term "QD" means once a day, once a day, or once daily.

[0036] "T max The term "peak plasma concentration (C max ) refers to the time.

[0037] The terms "treatment," "treating," and "treatment" refer to ameliorating, suppressing, eradicating, reducing the severity of, reducing the frequency of, lowering the risk of, or delaying the onset of a condition.

[0038] The abbreviations listed in Table 1 below have the meanings indicated in the table.

[0039] [Table 1]

[0040] II. Solid Dosage Forms The present disclosure relates, in part, to solid pharmaceutical dosage forms comprising acalabrutinib maleate, particularly crystalline acalabrutinib maleate monohydrate. According to the Biopharmaceutics Classification System ("BCS"), acalabrutinib is a BCS Class II drug substance, meaning it exhibits good permeability but low solubility in the gastrointestinal tract. See Pepin, XJH, et al., "Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part II. A mechanistic PBPK model for IR formulation comparison, proton pump inhibitor drug interactions, and administration with acidic juices," European Journal of Pharmaceutics and Biopharmaceutics 142;435-448 (2019). The bioavailability of BCS Class II drug substances, including acalabrutinib, is generally limited by their dissolution rate and / or solvation. Additionally, acalabrutinib free base exhibits pH-dependent solubility, decreasing as the pH increases to its maximally basic pKa (i.e., approximately pH 6, where acalabrutinib is largely unionized). Increased gastric pH in subjects taking CALQUENCE® (e.g., subjects also taking a proton pump inhibitor or other gastric acid-reducing agent) may decrease the solubility of acalabrutinib in the stomach, potentially resulting in decreased bioavailability and / or increased intra- and inter-patient pharmacokinetic variability of acalabrutinib. The present disclosure relates to the unexpected discovery that solid pharmaceutical dosage forms containing acalabrutinib maleate, as described below, have acceptable physical and pharmacological properties (e.g., dissolution, stability, manufacturability, pharmacokinetics, etc.) and are substantially bioequivalent to the currently marketed CALQUENCE® capsule dosage form under normal acidic gastric conditions, while resulting in less variability in the pharmacokinetics of acalabrutinib over a wider range of gastric pH conditions.These solid dosage forms offer additional therapeutic options for treating conditions including B-cell malignancies such as chronic lymphocytic leukemia, small lymphocytic leukemia, and mantle cell lymphoma.

[0041] In some embodiments, the disclosure provides a solid pharmaceutical dosage form for oral administration to a human comprising about 75 mg to about 125 mg (free base equivalent) of acalabrutinib maleate and at least one pharmaceutically acceptable excipient, wherein the dosage form comprises: conditions in which at least about 75% of acalabrutinib maleate dissolves within about 30 minutes as measured in an in vitro dissolution test conducted using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and The present invention relates in part to a solid pharmaceutical dosage form that meets the conditions that at least about 75% of acalabrutinib maleate dissolves within about 60 minutes as measured in an in vitro dissolution test conducted using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM. The 0.1 N hydrochloric acid dissolution medium is considered to represent a fasting stomach, while the 5 mM phosphate pH 6.8 dissolution is considered to represent a worst case stomach treated with a gastric acid reducing agent. conditions in which at least about 75% of acalabrutinib maleate dissolves within about 20 minutes as measured in an in vitro dissolution test conducted using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and At least about 75% of acalabrutinib maleate is dissolved within about 45 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM. In another aspect, the dosage form comprises: conditions in which at least about 80% of acalabrutinib maleate dissolves within about 20 minutes as measured in an in vitro dissolution test conducted using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and At least about 80% of acalabrutinib maleate dissolves within about 30 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM. In another aspect, the dosage form comprises: conditions in which at least about 80% of acalabrutinib maleate dissolves within about 15 minutes as measured in an in vitro dissolution test conducted using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and At least about 80% of acalabrutinib maleate dissolves within about 20 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM.

[0042] In some embodiments, the solid pharmaceutical dosage form of the present disclosure comprises about 75 mg to about 125 mg of acalabrutinib maleate (free base equivalent). In one aspect, the dosage form comprises about 75 mg to about 100 mg of acalabrutinib maleate (free base equivalent). In another aspect, the dosage form comprises about 75 mg to about 80 mg of acalabrutinib maleate (free base equivalent). In another aspect, the dosage form comprises about 80 mg to about 85 mg of acalabrutinib maleate (free base equivalent). In another aspect, the dosage form comprises about 85 mg to about 90 mg of acalabrutinib maleate (free base equivalent). In another aspect, the dosage form comprises about 90 mg to about 95 mg of acalabrutinib maleate (free base equivalent). In another embodiment, the dosage form comprises about 95 mg to about 100 mg of acalabrutinib maleate (free base equivalent). In another embodiment, the dosage form comprises about 75 mg of acalabrutinib maleate (free base equivalent). In another embodiment, the dosage form comprises about 80 mg of acalabrutinib maleate (free base equivalent). In another embodiment, the dosage form comprises about 85 mg of acalabrutinib maleate (free base equivalent). In another embodiment, the dosage form comprises about 90 mg of acalabrutinib maleate (free base equivalent). In another embodiment, the dosage form comprises about 95 mg of acalabrutinib maleate (free base equivalent). In another embodiment, the dosage form comprises about 100 mg of acalabrutinib maleate (free base equivalent).

[0043] In some embodiments, the acalabrutinib maleate is acalabrutinib maleate monohydrate. In one aspect, the acalabrutinib maleate monohydrate is crystalline acalabrutinib maleate monohydrate. In another embodiment, the crystalline acalabrutinib maleate has peak positions measured in °2θ±0.2°2θ of 5.3, 9.8, 10.6, 11.6, 13.5, 13.8, 13.9, 14.3, 15.3, 15.6, 15.8, 15.9, 16.6, 17.4, 17.5, 18.7, 19.3, 19.6, 19.8, 20.0, 20.9, 21.3, 22.1, 22.3, 22.7, 23.2, 23.4, 23.7, 23.9, 24.5, 24. crystalline acalabrutinib maleate monohydrate Form A having an X-ray powder diffraction pattern consisting of one or more peaks selected from the group consisting of X-ray powder diffraction patterns having at least five peaks selected from the group consisting of: 8, 25.2, 25.6, 26.1, 26.4, 26.7, 26.9, 27.1, 27.6, 28.8, 29.5, 30.0, 30.3, 30.9, 31.5, 31.9, 32.5, 34.0, and 35.1. In another embodiment, crystalline acalabrutinib maleate monohydrate Form A has an X-ray powder diffraction pattern consisting of peaks at 5.3, 9.8, 10.6, 11.6, and 19.3 °2θ ± 0.2 °2θ. In another embodiment, the X-ray powder diffraction pattern is substantially in agreement with the X-ray powder diffraction pattern of Figure 1. In another aspect, the X-ray powder diffraction pattern of any of the foregoing embodiments is measured in transmission mode. In another aspect, the X-ray powder diffraction pattern of any of the foregoing embodiments is measured in reflection mode. In another aspect, the crystalline acalabrutinib maleate monohydrate of any of the foregoing embodiments has a stoichiometry with respect to acalabrutinib that is approximately equivalent to the monohydrate. WO 2017 / 002095 describes applicable X-ray powder diffraction measurement conditions.

[0044] In some embodiments, the dosage form comprises acalabrutinib maleate having a crystalline purity of at least about 80% by weight of the acalabrutinib present in the dosage form. In one aspect, the crystalline purity is at least about 85% by weight. In another aspect, the crystalline purity is at least about 90% by weight. In another aspect, the crystalline purity is at least about 95% by weight. In another aspect, the crystalline purity is at least about 98% by weight. In another aspect, the crystalline purity is at least about 99% by weight. In another aspect, the acalabrutinib maleate is acalabrutinib maleate monohydrate. In another aspect, the acalabrutinib maleate is acalabrutinib maleate monohydrate Form A.

[0045] In some embodiments, the dosage form comprises acalabrutinib maleate having a crystalline purity of at least about 95% by weight of the acalabrutinib present in the dosage form. In one aspect, the acalabrutinib maleate is acalabrutinib maleate monohydrate. In another aspect, the acalabrutinib maleate is acalabrutinib maleate monohydrate Form A. In another aspect, the crystalline purity is at least about 96% by weight. In another aspect, the crystalline purity is at least about 97% by weight. In another aspect, the crystalline purity is at least about 98% by weight. In another aspect, the crystalline purity is at least about 99% by weight. In a further embodiment, the acalabrutinib maleate has a crystalline purity of at least about 95% by weight of the acalabrutinib present in the dosage form and contains less than 2% by weight of the impurity, (2Z)-4-[(2S)-2-{8-amino-1-[4-(2-pyridinylcarbamoyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}-1-pyrrolidinyl]-4-oxo-2-butenoic acid, having the chemical structure shown below: [ka] In another embodiment, the acalabrutinib maleate contains less than about 1.5% by weight of impurities. In another embodiment, the acalabrutinib maleate contains less than about 1% by weight of impurities. In another embodiment, the acalabrutinib maleate contains less than about 0.5% by weight of impurities. In another embodiment, the acalabrutinib maleate is substantially free of impurities.

[0046] Selecting a salt of a compound rather than the free form of the compound does not necessarily improve the solubility and uptake of the compound in the gastrointestinal tract to the desired degree. Furthermore, salts of a compound may differ significantly in physical and other properties that affect whether the salt is suitable for use in a pharmaceutical dosage form. For example, rapid conversion of a salt to the relatively insoluble free form in the acidic environment of the stomach and the intestinal environment at pH 6 to pH 7.5 can result in precipitation of some of the free form. Such precipitation of the free form reduces the amount of the administered dose available for uptake in the gastrointestinal tract, reducing the overall bioavailability of the compound. Surface properties (e.g., affecting wettability) and particle size (e.g., affecting dissolution rate) are also among the factors that can affect the performance of a salt selected for a dosage form.

[0047] For example, it has been determined that the citrate, fumarate, gentisate, napadisylate, nitrate, oxalate, phosphate, sulfate, and L-tartrate salts of acalabrutinib are all unsuitable for use in the solid pharmaceutical dosage forms of the present disclosure. a Salts were eliminated from consideration based on evidence of low hydration values ​​and / or complex solid-state behavior. For example, napadisylate had crystallinity issues. Nitrate salts may not be suitable for scale manufacturing and are generally not preferred for pharmaceutical use. Oxalate, phosphate, and sulfate salts exhibit complex hydration behavior and were deemed unsuitable for commercial manufacturing.

[0048] Indeed, the initial acalabrutinib maleate samples tested were unlikely to achieve the solubility and dissolution rate required to overcome the limitations of acalabrutinib free base in patients with elevated gastric pH. Furthermore, crystalline acalabrutinib maleate monohydrate Form A, while thermodynamically stable under ambient conditions, also exhibits solid-state properties that were initially thought to pose challenges to the manufacture of a commercial supply of the formulation.

[0049] In some embodiments, the disclosure relates to a solid pharmaceutical dosage form in which the dissolution rate of acalabrutinib maleate in an in vitro dissolution test using a USP Paddle Apparatus 2, a 900 mL dissolution volume, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM does not decrease by more than 20% from its initial dissolution rate after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In one aspect, the dissolution rate does not decrease by more than 10% from its initial dissolution rate after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In one aspect, the dissolution rate does not decrease by more than 15% from its initial dissolution rate after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In another aspect, the dissolution rate does not decrease by more than 5% from its initial dissolution rate after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In another embodiment, the dissolution rate does not decrease by more than 3% from its initial dissolution rate after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In another embodiment, the dissolution rate does not decrease by more than 2% from its initial dissolution rate after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In another embodiment, the dissolution rate does not decrease by more than 1% from its initial dissolution rate after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In one embodiment, the package is a blister package, such as an aluminum blister. In another embodiment, the package is a sealed HDPE bottle with a desiccant.

[0050] In some embodiments, the disclosure relates to solid pharmaceutical dosage forms in which no more than about 5% (w / w) of the acalabrutinib maleate present in the dosage form degrades after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In one aspect, no more than about 3% (w / w) of the acalabrutinib maleate present in the dosage form degrades after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In another aspect, no more than about 2% (w / w) of the acalabrutinib maleate present in the dosage form degrades after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In another aspect, no more than about 1% (w / w) of the acalabrutinib maleate present in the dosage form degrades after the dosage form is stored in a blister pack at 40°C and 75% relative humidity for 6 months. In another embodiment, after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months, no more than about 0.5% (w / w) of the acalabrutinib maleate present in the dosage form is degraded. In one embodiment, the packaging is a blister package, such as an aluminum blister. In another embodiment, the packaging is a sealed HDPE bottle containing a desiccant. In another embodiment, the degradation of acalabrutinib maleate is analyzed using high performance liquid chromatography.

[0051] In some embodiments, the disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form is substantially bioequivalent to a 100 mg Calquence® capsule (a composition corresponding to the content of reference capsule C4 in Table 6 of Example 4) when orally administered to fasted human subjects not receiving a gastric acid reducing agent. In one aspect, the dosage form, when orally administered to fasted human subjects not receiving a gastric acid reducing agent, has a relative mean C of the dosage form within the range of 80% to 125% of that of a 100 mg Calquence® capsule of plasma acalabrutinib. max , AUC (0-t) , and AUC (0-∞)In another aspect, the dosage form, when orally administered to fasted human subjects not receiving a gastric acid reducing agent, has a relative mean C of the dosage form relative to a 100 mg Calquence® capsule of plasma acalabrutinib and its active metabolite ACP-5862 (i.e., 4-[8-amino-3-[4-(but-2-ynoylamino)butanoyl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide) within the range of 80% to 125%. max , AUC (0-t) , and AUC (0-∞) has a confidence interval of

[0052] In some embodiments, the present disclosure provides a dosage form that, when administered twice daily to a population of fasting human subjects, Mean C for a population of human subjects max a value of about 400 ng / mL to about 900 ng / mL; Mean AUC for a population of human subjects (0-24) a value of about 350 ng·hr / mL to about 1900 ng·hr / mL; and / or Mean AUC for a population of human subjects (0-∞) The present invention relates to a solid pharmaceutical dosage form that satisfies one or more of the pharmacokinetic conditions of acalabrutinib, wherein the pharmacokinetic value is between about 350 ng·hr / mL and about 1900 ng·hr / mL. In one embodiment, the dosage form is co-administered with a gastric acid reducing agent to a population of human subjects.

[0053] In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form provides a median steady-state Bruton's tyrosine kinase occupancy in peripheral blood mononuclear cells of at least about 90% when administered twice daily (BID) to a human subject. In one aspect, the dosage form provides a median steady-state Bruton's tyrosine kinase occupancy in peripheral blood mononuclear cells of at least about 95% when administered twice daily to a human subject. In another aspect, the dosage form is co-administered with a gastric acid reducing agent to a population of human subjects.

[0054] In some embodiments, the disclosure relates to solid pharmaceutical dosage forms in which acalabrutinib maleate is present in an amount of about 15% to about 55% (free base equivalent) by weight of the dosage form. In one aspect, acalabrutinib maleate is present in an amount of about 25% to about 50% by weight of the dosage form. In another aspect, acalabrutinib maleate is present in an amount of about 25% to about 45% by weight of the dosage form. In another aspect, acalabrutinib maleate monohydrate is present in an amount of about 25% to about 40% by weight of the dosage form.

[0055] In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form in which the at least one pharmaceutically acceptable excipient is selected from at least one diluent, at least one disintegrant, and at least one lubricant. In one aspect, the at least one pharmaceutically acceptable excipient comprises at least one diluent. In another aspect, the at least one pharmaceutically acceptable excipient comprises at least one disintegrant. In another aspect, the at least one pharmaceutically acceptable excipient comprises at least one diluent and at least one disintegrant. In another aspect, the at least one pharmaceutically acceptable excipient comprises at least one diluent, at least one disintegrant, and at least one lubricant. The interaction of excipients in a dosage form may in some cases affect the compatibility of the excipient combination in the dosage form of the present disclosure. Therefore, it is preferred that the selected excipient combination does not substantially affect the suitability of the dosage form for pharmaceutical use.

[0056] In some embodiments, the present disclosure relates to solid pharmaceutical dosage forms wherein the dosage comprises at least one diluent, and wherein the at least one diluent is present in an amount of about 10% to about 70% by weight of the dosage form. In one aspect, the at least one diluent is present in an amount of about 20% to about 70% by weight of the dosage form. In another aspect, the at least one diluent is present in an amount of about 30% to about 70% by weight of the dosage form. In another aspect, the at least one diluent is present in an amount of about 40% to about 70% by weight of the dosage form. In another aspect, the weight ratio of acalabrutinib maleate to the at least one diluent is about 1:3 to about 2:1. In another aspect, the weight ratio of acalabrutinib maleate monohydrate to the at least one diluent is about 1:1 to about 1:2.

[0057] When present, the selected diluent preferably does not affect the stability of the primary amine moieties of acalabrutinib. In one embodiment, the diluent is one that is unlikely to react with the primary amine moieties in the Maillard reaction. For example, the diluent is not a reducing sugar such as lactose. In addition, the diluent preferably does not contain a maleic acid scavenger such as a metal salt. In one embodiment, the diluent does not contain anhydrous calcium hydrogen phosphate. Acceptable diluents include, for example, sugar alcohols (such as mannitol, sorbitol, maltitol, and xylitol), hydrolyzed starch, partially pregelatinized starch and cellulose (such as microcrystalline cellulose and silicified microcrystalline cellulose), and combinations thereof (such as a combination comprising mannitol and starch).

[0058] In some embodiments, the at least one diluent comprises a plastic diluent and a brittle diluent. Plastic diluents, such as microcrystalline cellulose, undergo irreversible deformation during compression after the yield point is exceeded, causing the particles to flow viscously and remain deformed after the compression force is removed. Brittle diluents, such as mannitol, fragment during compression, creating new surfaces for particle bonding. In one aspect, the dosage form comprises a plastic diluent and a brittle diluent in a total amount of about 10% to about 70% by weight of the dosage form, with the plastic diluent being present in an amount of about 0% to about 70% by weight of the dosage form and the brittle diluent being present in an amount of about 0% to about 50% by weight of the dosage form. When the dosage form is a tablet, the ratio of plastic diluent to brittle diluent selected can affect the tensile strength of the tablet. Excessive plastic diluent can weaken the tensile strength of the tablet. In one embodiment, the w / w ratio of plastic diluent to brittle diluent in the dosage form is from about 0:100 to about 60:40. In another embodiment, the w / w ratio of plastic diluent to brittle diluent in the dosage form is from about 0:100 to about 60:40, and the dosage form is a tablet having a tensile strength of at least 2.0 MPa.

[0059] In some embodiments, the at least one diluent comprises mannitol. In one aspect, the mannitol is present in an amount of about 10% to about 70% by weight of the dosage form.

[0060] In some embodiments, the at least one diluent comprises microcrystalline cellulose. In one aspect, the microcrystalline cellulose is present in an amount of about 5% to about 50% by weight of the dosage form.

[0061] In some embodiments, the at least one diluent comprises mannitol and microcrystalline cellulose. In one aspect, the mannitol is present in an amount of about 0% to about 70% by weight of the dosage form, the microcrystalline cellulose is present in an amount of about 0% to about 50% by weight of the dosage form, and the total amount of mannitol and microcrystalline cellulose is about 10% to about 70% by weight of the dosage form. In another aspect, the w / w ratio of mannitol to microcrystalline cellulose is about 0:100 to about 60:40. In another aspect, the w / w ratio of mannitol to microcrystalline cellulose in the dosage form is about 0:100 to about 60:40, and the dosage form is a tablet having a tensile strength of at least 2.0 MPa.

[0062] In some embodiments, the present disclosure relates to solid pharmaceutical dosage forms comprising at least one disintegrant, wherein the at least one disintegrant is present in an amount of about 0.5% to about 15% by weight of the tablet. In one aspect, the at least one disintegrant is present in an amount of about 1% to about 10% by weight of the tablet. In another aspect, the at least one disintegrant is present in an amount of about 2% to about 8% by weight of the tablet. In another aspect, the at least one disintegrant is present in an amount of about 3% to about 7% by weight of the tablet. In another aspect, the weight ratio of acalabrutinib maleate (free base equivalent) to the at least one disintegrant is about 2:1 to about 15:1. In another aspect, the weight ratio of acalabrutinib maleate to the at least one disintegrant is about 4:1 to about 10:1.

[0063] If present, the selected disintegrant preferably does not include an ionic disintegrant. In one embodiment, at least one disintegrant does not include sodium starch glycolate and / or croscarmellose sodium. In one embodiment, at least one disintegrant does not include sodium starch glycolate. In another embodiment, at least one disintegrant does not include croscarmellose sodium. Acceptable disintegrants include, for example, hydroxypropyl cellulose, corn starch, microcrystalline cellulose, crospovidone, and combinations thereof. In one embodiment, at least one disintegrant includes hydroxypropyl cellulose. In another embodiment, at least one disintegrant includes low-substituted hydroxypropyl cellulose.

[0064] In some embodiments, the present disclosure relates to solid pharmaceutical dosage forms comprising at least one lubricant, wherein the at least one lubricant is present in an amount of about 0.25% to about 4% by weight of the dosage form. In one aspect, the at least one lubricant is present in an amount of about 1% to about 4% by weight of the dosage form. In another aspect, the at least one lubricant is present in an amount of about 1.5% to about 3.5% by weight of the dosage form. In another aspect, the at least one lubricant is present in an amount of about 2% to about 3% by weight of the dosage form. In another aspect, the weight ratio of acalabrutinib maleate (free base equivalent) to the at least one lubricant is about 20:1 to about 12:1. In another aspect, the weight ratio of acalabrutinib maleate to the at least one lubricant is about 18:1 to about 14:1.

[0065] Acceptable lubricants include, for example, sodium stearyl fumarate, stearic acid, myristic acid, palmitic acid, sugar esters (such as sorbitan monostearate and sucrose monopalmitate), and combinations thereof. In another embodiment, at least one lubricant comprises sodium stearyl fumarate. Magnesium stearate should generally be avoided as a lubricant.

[0066] In some embodiments, the present disclosure provides a dosage form comprising: acalabrutinib maleate in an amount of about 15% to about 55% (free base equivalent) by weight of the dosage form; at least one diluent in an amount of about 10% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 0.5% to about 15% by weight of the dosage form; and at least one lubricant in an amount of about 0.25% to about 4% by weight of the dosage form; It relates to a solid pharmaceutical dosage form in which the sum of the individual amounts equals 100% of the total weight of the dosage form. In one aspect, the dosage form consists essentially of the ingredients set forth above. In a further aspect, the acalabrutinib maleate is present as acalabrutinib maleate monohydrate.

[0067] In some embodiments, the present disclosure provides a dosage form comprising: Acalabrutinib maleate monohydrate in an amount of about 20% to about 50% (free base equivalent) by weight of the dosage form; at least one diluent in an amount of about 20% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 1% to about 10% by weight of the dosage form; and at least one lubricant in an amount of about 1% to about 4% by weight of the dosage form; It relates to a solid pharmaceutical dosage form in which the sum of the individual amounts equals 100% of the total weight of the dosage form. In one aspect, the dosage form consists essentially of the ingredients set forth above. In a further aspect, the acalabrutinib maleate is present as acalabrutinib maleate monohydrate.

[0068] In some embodiments, the present disclosure provides a dosage form comprising: acalabrutinib maleate in an amount of about 25% to about 50% (free base equivalent) by weight of the dosage form; at least one diluent in an amount of about 30% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 2% to about 8% by weight of the dosage form; and at least one lubricant in an amount of about 1.5% to about 3.5% by weight of the dosage form; It relates to a solid pharmaceutical dosage form in which the sum of the individual amounts equals 100% of the total weight of the dosage form. In one aspect, the dosage form consists essentially of the ingredients set forth above. In a further aspect, the acalabrutinib maleate is present as acalabrutinib maleate monohydrate.

[0069] In some embodiments, the present disclosure provides a dosage form comprising: acalabrutinib maleate in an amount of about 25% to about 40% (free base equivalent) by weight of the dosage form; at least one diluent in an amount of about 40% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 3% to about 7% by weight of the dosage form; and at least one lubricant in an amount of about 2% to about 3% by weight of the dosage form; It relates to a solid pharmaceutical dosage form in which the sum of the individual amounts equals 100% of the total weight of the dosage form. In one aspect, the dosage form consists essentially of the ingredients set forth above. In a further aspect, the acalabrutinib maleate is present as acalabrutinib maleate monohydrate.

[0070] In some embodiments, the present disclosure provides a dosage form comprising: Acalabrutinib maleate in an amount of about 30% to about 35% (free base equivalent) by weight of the dosage form; and Mannitol in an amount of about 30% to about 35% by weight of the dosage form; microcrystalline cellulose in an amount of about 25% to about 30% by weight of the dosage form; hydroxypropyl cellulose in an amount of about 3% to about 7% by weight of the dosage form; and sodium stearyl fumarate in an amount of about 1% to about 4% by weight of the dosage form; It relates to a solid pharmaceutical dosage form in which the sum of the individual amounts equals 100% of the total weight of the dosage form. In one aspect, the dosage form consists essentially of the ingredients set forth above. In a further aspect, the acalabrutinib maleate is present as acalabrutinib maleate monohydrate.

[0071] In some embodiments, the present disclosure provides that acalabrutinib maleate has a D of less than about 500 microns. (v,0.9) In one embodiment, the acalabrutinib maleate has a D value of less than about 450 microns. (v,0.9) In another embodiment, the acalabrutinib maleate has a D value of less than about 400 microns. (v,0.9) In another embodiment, the acalabrutinib maleate has a D value of less than about 350 microns. (v,0.9) In another embodiment, the acalabrutinib maleate has a D value of less than about 300 microns. (v,0.9) In another embodiment, acalabrutinib maleate has a D value of about 20 microns to about 500 microns. (v,0.9) In another embodiment, acalabrutinib maleate has a D value of about 50 microns to about 450 microns. (v,0.9) In another embodiment, acalabrutinib maleate has a D value of about 75 microns to about 400 microns. (v,0.9) In another embodiment, acalabrutinib maleate has a D value of about 75 microns to about 350 microns. (v,0.9) In another embodiment, acalabrutinib maleate has a D value of about 100 microns to about 300 microns. (v,0.9) It has a value.

[0072] In some embodiments, the present disclosure provides that acalabrutinib maleate meets one or more of the following conditions: a D of less than about 20 microns (v,0.1) D value, less than about 145 microns (v,0.5) value, and D less than about 330 microns (v,0.9) In another embodiment, the solid pharmaceutical dosage form has a calcareous maleate content of less than about 145 microns. (v,0.5) value, and D less than 330 microns (v,0.9) In another embodiment, the acalabrutinib maleate has a D value of less than about 20 microns. (v,0.1) D value, less than about 145 microns (v,0.5) value, and D less than about 330 microns (v,0.9) It has a value.

[0073] In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form is a capsule. In one aspect, the capsule is prepared by a process including roller compaction.

[0074] In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form is a tablet. In one aspect, the dosage form is a film-coated tablet. In another aspect, the film coat is a stabilizing film coat. In another aspect, the tablet is prepared by a process comprising direct compression. In another aspect, the tablet is prepared by a process comprising roller compaction. In another aspect, the tablet is prepared by a process comprising wet granulation. In another aspect, the tablet has a tensile strength of about 1.5 MPa to about 5.0 MPa. In another aspect, the tablet has a tensile strength of about 2.0 MPa to about 4.0 MPa. In another aspect, the tensile strength of the tablet does not decrease by more than 10% from its initial tensile strength after the tablet is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In another aspect, the tensile strength of the tablet does not decrease by more than 8% from its initial tensile strength after the tablet is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In another embodiment, the tensile strength of the tablet does not decrease by more than 5% from its initial tensile strength after the tablet is stored in suitable packaging at 40°C and 75% relative humidity for 6 months. In one embodiment, the packaging is a blister package, such as an aluminum blister. In another embodiment, the packaging is a sealed HDPE bottle with a desiccant.

[0075] In some embodiments, the tablet is a coated or uncoated tablet having a core weight of less than about 600 mg. In another aspect, the dosage form is a coated or uncoated tablet having a core weight of about 300 mg to about 500 mg. In another aspect, the dosage form is a coated or uncoated tablet having a core weight of about 350 mg to about 450 mg. In another aspect, the dosage form is a coated or uncoated tablet having a core weight of about 400 mg.

[0076] III. Treatment method The present disclosure also relates to a method of treating a condition in a subject, particularly a human subject suffering from or susceptible to a BTK-mediated condition, comprising administering to the subject once or twice daily a solid pharmaceutical dosage form comprising acalabrutinib maleate as described in any of the embodiments of the present disclosure. In one aspect, the solid pharmaceutical dosage form comprising acalabrutinib maleate is administered once daily. In another aspect, the solid pharmaceutical dosage form comprising acalabrutinib maleate is administered twice daily.

[0077] In one embodiment, the present disclosure relates to a method of treating a condition in a subject, particularly a human subject suffering from or susceptible to a B-cell hematological malignancy, comprising administering to the subject once daily or twice daily a solid pharmaceutical dosage form comprising acalabrutinib maleate as described in any of the embodiments of the present disclosure. In one aspect, the solid pharmaceutical dosage form comprising acalabrutinib maleate is administered once daily. In another aspect, the solid pharmaceutical dosage form comprising acalabrutinib maleate is administered twice daily.

[0078] In some embodiments, the B-cell hematological malignancy is selected from the group consisting of non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), B-cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), multiple myeloma, myelodysplastic syndrome, and myelofibrosis.

[0079] In some embodiments, the B-cell hematological malignancy is non-Hodgkin's lymphoma. In one aspect, the non-Hodgkin's lymphoma is aggressive non-Hodgkin's lymphoma. In another aspect, the non-Hodgkin's lymphoma is indolent non-Hodgkin's lymphoma.

[0080] In some embodiments, the B-cell hematological malignancy is Hodgkin's lymphoma.

[0081] In some embodiments, the B-cell hematological malignancy is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic leukemia.

[0082] In some embodiments, the B-cell hematological malignancy is mantle cell lymphoma. In one aspect, the mantle cell lymphoma is mantle zone lymphoma. In one aspect, the mantle cell lymphoma is nodular mantle cell lymphoma. In another aspect, the mantle cell lymphoma is diffuse mantle cell lymphoma. In another aspect, the mantle cell lymphoma is blastic mantle cell lymphoma.

[0083] In some embodiments, the B-cell hematological malignancy is chronic lymphocytic leukemia.

[0084] In some embodiments, the B-cell hematological malignancy is small lymphocytic leukemia.

[0085] In some embodiments, the B-cell hematological malignancy is diffuse large B-cell lymphoma. In one aspect, the diffuse large B-cell lymphoma is selected from the group consisting of primary diffuse large B-cell lymphoma, relapsed / refractory diffuse large B-cell lymphoma, and transformed diffuse large B-cell lymphoma. In another aspect, the diffuse large B-cell lymphoma is primary diffuse large B-cell lymphoma. In another aspect, the diffuse large B-cell lymphoma is relapsed / refractory diffuse large B-cell lymphoma. In another aspect, the diffuse large B-cell lymphoma is transformed diffuse large B-cell lymphoma. In another aspect, the transformed diffuse large B-cell lymphoma is Richter's syndrome.

[0086] In some embodiments, the diffuse large B-cell lymphoma is selected from the group consisting of germinal center B-cell diffuse large B-cell lymphoma subtype and activated B-cell diffuse large B-cell lymphoma subtype. In one aspect, the diffuse large B-cell lymphoma is relapsed / refractory germinal center B-cell diffuse large B-cell lymphoma. In another aspect, the diffuse large B-cell lymphoma is relapsed / refractory activated B-cell diffuse large B-cell lymphoma.

[0087] In some embodiments, the B-cell hematological malignancy is follicular lymphoma.

[0088] In some embodiments, the B-cell hematological malignancy is Waldenstrom's macroglobulinemia.

[0089] In some embodiments, the B-cell hematological malignancy is B-cell acute lymphoblastic leukemia. In one aspect, the B-cell acute lymphoblastic leukemia is early pre-B-cell acute lymphoblastic leukemia. In another aspect, the B-cell acute lymphoblastic leukemia is pre-B-cell acute lymphoblastic leukemia. In another aspect, the B-cell acute lymphoblastic leukemia is mature B-cell acute lymphoblastic leukemia.

[0090] In some embodiments, the B-cell hematological malignancy is Burkitt lymphoma. In one aspect, the Burkitt lymphoma is sporadic Burkitt lymphoma. In another aspect, the Burkitt lymphoma is endemic Burkitt lymphoma. In another aspect, the Burkitt lymphoma is human immunodeficiency virus-associated Burkitt lymphoma.

[0091] Diagnosis of the particular B-cell malignancy a subject is suffering from can be made according to accepted clinical practice, e.g., see the 2016 classification guidelines established by the World Health Organization (WHO) for lymphoid neoplasms or the National Comprehensive Cancer Network (NCCN) classification guidelines for non-Hodgkin's lymphoma.

[0092] In some embodiments, the human subject has already received at least one prior chemoimmunotherapy for the B-cell malignancy. In one aspect, the prior chemoimmunotherapy comprises treatment with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). In another aspect, the prior chemoimmunotherapy comprises treatment with fludarabine, cyclophosphamide, and rituximab (FCR). In another aspect, the prior chemoimmunotherapy comprises treatment with rituximab and bendamustine (BR). In another aspect, the prior chemoimmunotherapy comprises treatment with chlorambucil and obinutuzumab.

[0093] In some embodiments, the human subject has already received treatment with a BTK inhibitor other than acalabrutinib (such as ibrutinib or zanubrutinib).

[0094] In another embodiment, the present disclosure relates to the use of a solid pharmaceutical dosage form comprising acalabrutinib maleate as described in any of the embodiments of the present disclosure for treating B-cell malignancies.

[0095] In another embodiment, the present disclosure relates to the use of a solid pharmaceutical dosage form comprising acalabrutinib maleate as described in any of the embodiments of the present disclosure in the manufacture of a medicament for treating a B-cell malignancy.

[0096] In some embodiments, a solid pharmaceutical dosage form comprising acalabrutinib maleate is co-administered to a subject with a gastric acid reducing agent, such as a proton pump inhibitor, an H2 receptor antagonist, or an antacid. In one aspect, the co-administration is simultaneous. In another aspect, the co-administration is sequential.

[0097] In some embodiments, the disclosure relates to a method of improving the pharmacokinetics of orally administered acalabrutinib over a wider range of acidic gastric conditions in a subject suffering from or susceptible to a B-cell hematological malignancy, the method comprising administering to the subject a solid pharmaceutical dosage form containing acalabrutinib maleate as described in any of the embodiments of the disclosure once daily (OD) or twice daily (BID). In one aspect, the method improves and / or reduces the variability in bioavailability of acalabrutinib within and / or between subjects. In another aspect, the method reduces the variability in the pharmacokinetics of acalabrutinib within and / or between subjects. In another aspect, the method improves and / or reduces the variability in the C max In another aspect, the method improves and / or reduces the variability of the T of acalabrutinib within and / or between subjects. max In another embodiment, the intra- and / or inter-subject AUC of acalabrutinib is improved and / or reduced. (0-∞) Improve and / or reduce fluctuations in

[0098] In some embodiments, the present disclosure relates to a method of treating a human subject infected with SARS-CoV-2 and / or having coronavirus disease 2019 (COVID-19), comprising administering to the subject a solid pharmaceutical dosage form containing acalabrutinib maleate as described in any of the embodiments of the present disclosure.

[0099] In another embodiment, the present disclosure relates to the use of a solid pharmaceutical dosage form comprising acalabrutinib maleate as described in any of the embodiments in a human subject infected with SARS-CoV-2 and / or with coronavirus disease 2019 (COVID-19).

[0100] In another embodiment, the present disclosure relates to the use of a solid pharmaceutical dosage form comprising acalabrutinib maleate as described in any of the embodiments of the present disclosure in the manufacture of a medicament for treating a human subject infected with SARS-CoV-2 and / or having coronavirus disease 2019 (COVID-19).

[0101] The disclosed methods also contemplate treatments comprising co-administering one or more additional therapeutic agents with a solid pharmaceutical dosage form comprising acalabrutinib maleate as described in any of the embodiments of the present disclosure. Accordingly, the dosage forms of the present disclosure can be administered alone or in combination with one or more additional therapeutic agents. When administered in combination with one or more additional therapeutic agents, the additional therapeutic agents may be administered simultaneously with the acalabrutinib maleate dosage form of the present disclosure, or sequentially with the acalabrutinib maleate dosage form of the present disclosure. In one aspect, the therapeutic agent is an anti-CD20 antibody. In another aspect, the anti-CD20 antibody is selected from the group consisting of rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ublituximab. In another embodiment, the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, and ofatumumab. In another embodiment, the anti-CD20 antibody is rituximab. In another embodiment, the anti-CD20 antibody is obinutuzumab. In another embodiment, the anti-CD20 antibody is ofatumumab.

[0102] IV. Kit The present disclosure further relates in part to kits comprising one or more solid pharmaceutical dosage forms comprising acalabrutinib maleate as described in any of the embodiments of the present disclosure. The kits may optionally include one or more additional therapeutic agents and / or instructions for using the kit. Suitable packaging and additional items for use are known in the art and may be included in the kits. Kits may be provided, sold, and / or recommended to healthcare providers, including doctors, nurses, pharmacists, and formulary officials.

[0103] In some embodiments, the kit comprises a semipermeable container containing one or more solid pharmaceutical dosage forms comprising acalabrutinib maleate. In one aspect, the semipermeable container is a blister package.

[0104] In some embodiments, the kit comprises a substantially impermeable container containing one or more solid pharmaceutical dosage forms comprising acalabrutinib maleate. In one aspect, the impermeable container is an HDPE bottle containing a desiccant.

[0105] In some embodiments, the kit comprises multiple individual packages (e.g., packages containing one or two solid dosage forms), each package containing a daily dose of a solid pharmaceutical dosage form comprising acalabrutinib maleate.

[0106] The kit described above is preferably used for treating a B-cell malignancy as described herein. For example, in one embodiment, the B-cell malignancy is non-Hodgkin's lymphoma. In another embodiment, the B-cell malignancy is mantle cell lymphoma. In another embodiment, the B-cell malignancy is chronic lymphocytic leukemia. In another embodiment, the B-cell malignancy is small lymphocytic leukemia. In another embodiment, the B-cell malignancy is diffuse large B-cell lymphoma.

[0107] In another embodiment, the kit described above is used to treat a human subject infected with SARS-CoV-2 and / or having coronavirus disease 2019 (COVID-19).

[0108] V. Preparation method The present disclosure also relates to methods for preparing solid pharmaceutical dosage forms comprising acalabrutinib maleate as described in this disclosure, such as those methods described in the Examples below. Generally, these dosage forms can be prepared using techniques such as, but not limited to, direct blending, dry granulation (roller compaction), wet granulation (high shear granulation), milling or sieving, drying (if wet granulation is used), compression, and optionally coating.

[0109] VI. Product by Process The present disclosure also relates to a solid pharmaceutical dosage form comprising acalabrutinib maleate prepared according to any of the methods described in this disclosure, including the methods described in the Examples below. [Example]

[0110] VII. Working Examples Example 1: Evaluation of acalabrutinib salts 1.Dissolution test A two-stage in vitro dissolution method known as the pH shift method was used to evaluate the phosphate, oxalate, and maleate salts of acalabrutinib. The initial medium was either deionized water or simulated gastric acid containing hydrochloric acid and sodium chloride and adjusted to a pH of 1.8. After 30 minutes of salt addition to the initial medium, the medium was then changed to FaSSIF-V2 medium by adding a two-fold concentration, resulting in a final pH of 6.5. FaSSIF-V2 medium contained a sodium phosphate buffer containing sodium chloride, sodium taurocholate, and lecithin. Dissolution testing was performed using a USP dissolution apparatus 2 (paddle) operating at 50 RPM at 37±0.5°C in 250 mL of medium for the first 30 minutes, and then in 500 mL of medium after the shift. Samples from the dissolution medium were removed from the aqueous phase at designated time points and assayed by HPLC. Figures 2 and 3 show the dissolution profiles of the three salts in simulated gastric acid / FaSSIF-V2 and deionized water / FaSSIF-V2 media, respectively. The three salts exhibited broadly similar performance in the low pH simulated gastric acid medium, but the maleate salt exhibited substantially reduced dissolution in neutral water media compared to the oxalate and phosphate salts.

[0111] 2. Physical property testing The physical properties of the phosphate, oxalate, and maleate salts of acalabrutinib were investigated, including physical stability, crystallinity, and particle habit.

[0112] Solid-state analysis of the phosphate salts showed complex hydration behavior near ambient conditions, with the solids switching between hydrated forms and converting from one crystalline form to a more highly hydrated crystalline form at relative humidity ("RH") above 20% RH, as evidenced by the dynamic vapor sorption ("DVS") plot in Figure 4. Thermogravimetric analysis ("TGA") showed that the more highly hydrated forms were physically unstable, rapidly dehydrating in less than 10 minutes in an open dish isothermal at 40°C, as evidenced by Figure 5. Standard TGA further indicated that batches of phosphate salts were often heterogeneous in terms of water content and, therefore, physical form. X-ray powder diffraction ("XRPD") demonstrated that both crystalline forms could be identified, as shown in Figure 6.

[0113] The oxalate salt also exhibited complex hydration behavior. TGA showed that the hydrate was highly unstable, as evidenced in Figure 7. Water loss indicated a half-life of 4 minutes under isothermal TGA conditions at 35°C, with an overall weight loss of 3.2% w / w. Water loss was consistent with approximately 1 mole of water per mole of oxalate salt. DVS showed conversion from one crystalline form to a more highly hydrated crystalline form at ambient humidity, as evidenced in Figure 8. Optical microscopy revealed the oxalate salt to have a very sharp, needle-like habit.

[0114] The maleate salt was isolated as a monohydrate. Isothermal TGA at 50°C showed that the monohydrate dehydrated, as shown in Figure 9A, although the dehydration rate was slower than that of the phosphate or oxalate salts at lower temperatures of 40°C and 35°C, respectively. Figure 9B shows TGA plots performed under an alternative set of conditions. Figure 10A shows a DVS plot of the maleate salt, indicating that the % w / w moisture change over the humidity range was lower than that observed for the phosphate or oxalate salts. Figure 10B shows a DVS plot of a higher quality sample of the maleate salt. The maleate salt crystal habit was large and blocky.

[0115] Although the phosphate and oxalate salts have been shown to dissolve substantially better than the maleate salt in neutral aqueous media, the physical properties of the phosphate and oxalate salts present greater challenges in developing pharmaceutically acceptable formulations containing acalabrutinib salts.

[0116] 3. Dissolution of micronized maleate Given the formulation challenges associated with the physical properties of the phosphate and oxalate salts, the maleate salt was retested after micronization using the pH-shift dissolution method described above. The D between the micronized maleate batch and the unmilled maleate batch tested was (v,0.9) Typical mean particle size distributions for the micronized maleate salts were typically about 18 μm and about 446 μm, respectively. Testing of samples of the micronized maleate salt using the same method conditions as described above showed significantly improved dissolution profiles (improved to an even greater extent than would be expected by one skilled in the art) compared to samples of the unmilled maleate salt. Figures 11 and 12 show the dissolution profiles of the micronized and unmilled maleate salts in simulated gastric acid / FaSSIF-V2 medium and deionized water / FaSSIF-V2 medium, respectively.

[0117] Example 2: Evaluation of the solubility of acalabrutinib maleate The solubility of acalabrutinib maleate was measured in unbuffered media and was found to be approximately 3 mg / mL at pH 4 and approximately 3 mg / mL at pH max was calculated to be 4.11. Furthermore, acalabrutinib maleate in unbuffered media starting at a pH greater than 4 and up to about pH 11 was buffered to a surface pH ranging from 3.8 to 5, and the solubility of acalabrutinib maleate in unbuffered media from pH 4 to pH 11 was measured to be maintained at about 3 mg / mL. In contrast, the solubility of acalabrutinib free base in unbuffered media decreased to less than about 0.1 mg / mL as the pH approached pH 6.

[0118] Additionally, the solubility of acalabrutinib maleate was measured in buffer solutions representative of the media used to dissolve acalabrutinib maleate tablets. The final pH was also found to be affected by the presence of acalabrutinib maleate; depending on the buffer used, acalabrutinib maleate could be supersaturated compared to the free base at an equivalent final pH, or could exhibit solubility values ​​similar to those of the free base at an equivalent final pH. For example, acalabrutinib maleate in acetate buffer at pH 4.5 was supersaturated with a solubility significantly higher than that of the free base at pH 4.5. The final pH and solubility of acalabrutinib maleate were adjusted by adjusting the phosphate concentration and final pH in the phosphate buffer; the values ​​observed in all conditions were similar to those of acalabrutinib free base at an equivalent final pH. Figure 13 shows the solubility versus final pH of acalabrutinib maleate and acalabrutinib free base in various buffer solutions.

[0119] Example 3: Physicochemical properties of acalabrutinib maleate monohydrate Selected physicochemical properties of acalabrutinib maleate monohydrate were measured and are reported in Table 2 below.

[0120] [Table 2]

[0121] Example 4: Acalabrutinib maleate tablets Tablets containing acalabrutinib maleate monohydrate and various excipients were prepared by either direct compression or roller compression and are further described below. Directly compressed tablets were uncoated, while roller compressed tablets were film coated. All tablets prepared contained a unit dose of acalabrutinib maleate monohydrate equivalent to approximately 100 mg.

[0122] A. Directly compressed tablets Tablets of the compositions described in Tables 3 and 4 were prepared by direct compression. Prior to tablet compression, all ingredients except the lubricant were blended, then screened through a sieve, and then blended again. The selected lubricant was added to this blend, which was then further blended to lubricate it. Tablets were compressed using a suitable tablet press and tooling appropriate for the desired tablet compression weight. If the tablets required further lubrication (i.e., if punch picking or sticking was observed), additional lubricant was applied to the outside of the tablet die.

[0123] [Table 3]

[0124] [Table 4]

[0125] B. Roller-compressed tablets Tablets having the composition listed in Table 5 were prepared by roller compaction. All ingredients except the lubricant were blended. The intragranular portion of the lubricant was screened and then added to the blend, which was then lubricated by further blending. The lubricated blend was roller compacted to form ribbons, which were subsequently milled into granules. The extragranular portion of the lubricant was screened and then added to the granules, which were then lubricated by further blending. Tablet cores were compressed to a target compaction weight and force of 400 mg and 14 kN using 13 x 7.5 mm oval tablet tooling. The resulting tablet cores were film coated with a 3% to 4% weight gain of the coating suspension.

[0126] [Table 5]

[0127] C. Roller-compressed capsules In addition to the tablets described above, standard capsules containing acalabrutinib free base and having the composition set forth in Table 6 were prepared and used in some of the following examples. All ingredients except the lubricant were blended, then screened through a sieve, and then blended again. The selected lubricant was added to this blend, which was then lubricated by further blending. The lubricated blend was fed into a roller compactor, and the resulting ribbons were subsequently milled to produce granules suitable for encapsulation. Once the selected extragranular lubricant was blended and lubricated with the acalabrutinib granules, they were filled into size 1 hard gelatin capsules using encapsulation equipment to a target fill weight of 240 mg (i.e., 100 mg of acalabrutinib free base).

[0128] [Table 6]

[0129] D. Film-coated tablets T21 Further examples of film-coated dosage forms (T21) are set forth in Table 7 below.

[0130] [Table 7]

[0131] Example 5: Evaluation of in vitro dissolution profiles In vitro dissolution studies were conducted to evaluate the dissolution profile of acalabrutinib maleate formulations under low and high pH conditions. The pH conditions were selected to mimic the gastric pH conditions when the tablets are administered alone (low pH conditions) or co-administered with a proton pump inhibitor or a reducing agent (high pH conditions). Details of the dissolution studies are described below.

[0132] 1. Low pH 0.1N HCl dissolution test Figure 14 shows the dissolution profiles obtained from low pH studies under sink conditions for acalabrutinib maleate tablets T16, T17, and T18, and acalabrutinib free base capsules C1. Dissolution studies were performed using USP dissolution apparatus 2 (paddles) operating at 50 RPM at 37±0.5°C with 900 mL of dissolution medium containing 0.1 N hydrochloric acid. Samples from the dissolution medium were removed from the aqueous phase at predetermined time points and assayed by either HPLC or UV / visible spectroscopy. The results show that acalabrutinib maleate tablets and acalabrutinib free base capsules under low pH conditions have similar dissolution profiles.

[0133] 2. Low ionic strength 5mM phosphate pH 6.8 elution test at neutral pH Figure 15 shows the dissolution profiles obtained from low ionic strength testing of acalabrutinib maleate tablets T16, T17, and T18 at neutral pH under sink conditions. Dissolution testing was performed using USP dissolution apparatus 2 (paddles) operating at 75 RPM at 37±0.5°C with 900 mL of dissolution medium containing 5 mM sodium phosphate adjusted to pH 6.8. Samples from the dissolution medium were removed from the aqueous phase at predetermined time points and assayed by UV / visible spectroscopy. The results show that these acalabrutinib maleate tablets, when tested under high pH conditions, substantially maintained the dissolution profile exhibited under low pH conditions.

[0134] 3. High ionic strength 50 mM phosphate pH 6.8 elution test at neutral pH Figure 16 shows the dissolution profiles obtained from high ionic strength testing at neutral pH for acalabrutinib maleate tablets T13 and acalabrutinib free base capsules C2. Dissolution testing was performed using USP dissolution apparatus 2 (paddles) operating at 75 RPM at 37±0.5°C with 900 mL of dissolution medium containing 50 mM sodium phosphate adjusted to pH 6.8. Samples from the dissolution medium were removed from the aqueous phase at predetermined time points and assayed by HPLC. The results demonstrate an improved dissolution profile under high pH conditions for acalabrutinib maleate tablets compared to acalabrutinib free base capsules.

[0135] 4. Water elution test Figure 17 shows the dissolution profiles obtained in unbuffered neutral medium (i.e., conditions similar to a proton pump inhibitor-treated stomach) for acalabrutinib maleate tablets T1 and acalabrutinib free base capsules C1. Dissolution tests were performed with 300 mL of dissolution medium containing deionized water using USP dissolution apparatus 2 (paddles) operated at 50 RPM and 37±0.5°C. Samples from the dissolution medium were removed from the aqueous phase at predetermined time points and assayed by HPLC.

[0136] Figure 18 shows the dissolution profiles obtained from unbuffered neutral media for acalabrutinib maleate tablet T13 and acalabrutinib free base capsule C1. Dissolution testing of tablet T13 was performed in a dissolution medium volume of 900 mL containing deionized water using USP dissolution apparatus 2 (paddles) operated at 75 RPM and 37±0.5°C, and compared to reference capsule C1, which was tested at 300 mL and 50 RPM. Samples from the dissolution medium were removed from the aqueous phase at predetermined time points and assayed by HPLC.

[0137] The results presented in Figures 17 and 18 demonstrate an improved dissolution profile under high pH conditions for acalabrutinib maleate tablets compared to acalabrutinib free base capsules.

[0138] 5. Biological media testing The dissolution of acalabrutinib maleate tablet T19 was evaluated under gastric conditions associated with the acidic gastric compartment and with concomitant administration of a proton pump inhibitor or reducing agent. The initial media used were either simulated gastric acid containing hydrochloric acid and sodium chloride adjusted to a pH of 1.8, or a low-buffer capacity medium designed to mimic a stomach treated with a proton pump inhibitor (see Segregur D., et al., "Impact of Acid-Reducing Agents on Gastrointestinal Physiology and Design of Biorelevant Dissolution Tests to Reflect These Changes," J. Pharm. Sci., 108(11);2461-3477 (2019)). The PPI buffer was maleate-based and contained sodium chloride adjusted to pH 6. After 30 minutes in the initial medium, tablet T19 was converted to FaSSIF-V2 medium by adding 2x the amount of concentrate, resulting in a final pH of 6.5. FaSSIF-V2 medium contained sodium phosphate buffer with sodium chloride, sodium taurocholate, and lecithin. Dissolution testing was performed in 250 mL for the first 30 minutes, then 500 mL after the shift, using a USP dissolution apparatus 2 (paddle) operated at 75 RPM at 37±0.5°C. Samples from the dissolution medium were removed from the aqueous phase at predetermined time points and assayed by HPLC. After the pH shift to FaSSIF-V2 in both starting media, acalabrutinib (100 mg free base equivalent dose) was supersaturated without precipitation for at least another 90 minutes, as evidenced in Figure 19.

[0139] In separate dissolution tests, acalabrutinib maleate tablets T19 and acalabrutinib free base capsules C3 were evaluated under identical pH shift conditions as described above, using simulated gastric acid pH 1.8 as the initial medium. Figure 20 reports the results showing that the maleate tablets have comparable in vitro dissolution performance to the free base capsules under biorelevant conditions corresponding to the fasted stomach.

[0140] Overall, the in vitro dissolution results demonstrate that the dissolution profiles of acalabrutinib maleate tablets tested under low and high pH conditions are substantially equivalent, further suggesting that such tablets are bioequivalent when administered alone or co-administered with a proton pump inhibitor or a reducing agent.

[0141] Example 6: Evaluation in the TIM-1 model Testing was performed using the TNO TIM-1 (TIM-1) system, an important tool for cascade testing to build a mechanistic understanding of product performance in vitro and validate the clinical relevance of selected in vitro methods. The TIM-1 system has been described extensively in the literature. See, for example, Barker, R., et al., "Application and validation of an advanced gastrointestinal in vitro model for the evaluation of drug product performance in pharmaceutical development," J. Pharm. Sci., Volume 103, Issue 11, 15, Pages 3704-3712 (September 2014). The TIM-1 system is a multi-compartment, dynamic system that utilizes in vivo-relevant media, volume, pH, and fluid dynamics to mimic conditions found in the adult human upper gastrointestinal tract. This system also mimics a hollow fiber ultrafiltration absorptive sink. Volume, medium composition, excretion rate, temperature and pH are all dynamically computer controlled, allowing for the characterization of different subject physiologies, such as fasting, postprandial, or a variety of other more complex disease states.

[0142] More specifically, to assess the relative potency of acalabrutinib maleate tablets T19 and acalabrutinib free base capsules C2, the study was conducted in the TIM-1 system and evaluated under gastric conditions associated with an acidic gastric compartment and also with concomitant administration of a proton pump inhibitor or reducing agent. The conditions selected were representative of human gastric pH values ​​of 2 and 6. Gastric emptying was set in the "rapid" mode, which represents the most challenging situation for the formulation in terms of pH shift. This allows for the t 1 / 2 This means that the time required for absorption to reach the target tissue was 15 minutes, which is typical of the in vivo situation in fasted adults. Test substances were administered to the TIM-1 system, and the selected protocol was run for 300 minutes. The system was then run automatically, and samples were collected from the absorption compartment and assayed by HPLC every 60 minutes.

[0143] Figure 21 shows that the potency of acalabrutinib maleate tablets was comparable to that of acalabrutinib free base capsules at low pH (pH 2) conditions, and was not affected by high pH (pH 6) conditions, demonstrating that acalabrutinib maleate tablets did not precipitate during the pH shift caused by gastric emptying into the duodenum.

[0144] Example 7: Effect of particle size and drug loading on dissolution rate A study was performed to evaluate the effect of drug substance particle size and drug substance loading on the in vitro dissolution of acalabrutinib maleate tablets. The tablets evaluated had a D particle size ranging from 16 microns to 500 microns. (v,0.9) The tablets contained acalabrutinib maleate (100 mg base equivalent) with particle size (measured by laser diffraction) and a drug load of either 26% or 43% by weight. Dissolution studies were performed in 900 mL of 5 mM sodium phosphate buffer medium using a USP2 dissolution apparatus (paddles) operated at 75 RPM and 37±0.5°C.

[0145] Acalabrutinib maleate tablets T9, T10, T11, T12, T13, T14, and T15 were evaluated in this study. The particle size of the drug substance and drug load for each tablet are summarized in Table 8 below.

[0146] [Table 8]

[0147] Figure 22 further shows the particle size distribution of acalabrutinib maleate tablets T10, T11, T13, and T15. The tablets evaluated for the effect of drug loading were acalabrutinib maleate tablets T10, T11, T13, and T15 (26% drug load by weight) and acalabrutinib maleate tablets T9, T2, and T14 (43% drug load by weight), respectively. Figures 23 and 24 show the results of dissolution tests for acalabrutinib maleate tablets T10, T11, T13, and T15 (26% drug load by weight) and acalabrutinib maleate tablets T9, T12, and T14 (43% drug load by weight), respectively. Although the dissolution rate of tablets generally decreases as the particle size of acalabrutinib maleate increases, this observation did not hold true for the tablet with the finest acalabrutinib particle size (T11). One possible explanation for the difference in the results for tablet T11 is that the initially fast dissolution rate was reduced due to a lack of drug wettability. (v,0.9) The in vitro dissolution rates of acalabrutinib maleate tablets with particle size distributions in the range of 26% wt% to 43% wt% remained relatively constant as the drug loading increased.

[0148] Example 8: GastroPlus modeling and simulation of acalabrutinib exposure Software modeling and simulation studies were conducted to predict acalabrutinib exposure in human subjects following administration of the acalabrutinib maleate tablets (i.e., T10, T11, T13, and T15) of Example 7. Using the tablet dissolution rate data obtained in Example 7, a batch-specific formulation particle size distribution ("P-PSD") for each tablet was derived according to the method described by Pepin, et al. (Pepin, XJH, et al., "Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part I. Mechanistic modeling of drug product dissolution to derive a P-PSD for PBPK model input," Eur. J. Pharm. Biopharm., 142:421-434 (2019)), and the solubility was determined to be 2.144 mg / mL. The derived P-PSDs were then used as inputs into the PBPK model described by Pepin et al. (Pepin, XJH, et al. "Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part II. A mechanistic PBPK model for IR formulation comparison, proton pump inhibitor drug interactions, and administration with acidic juices," Eur. J. Pharm. and Biopharm., 142:435-448 (2019)) to predict human exposure to acalabrutinib for each tablet.

[0149] In the simulation, T10, T11, T13, and T15 tablets at 100 mg free base equivalent under acidic gastric conditions all exhibited the same mean AUC and C of acalabrutinib free base reference capsule C4. max The mean AUC and C values ​​correspond to maxTable 9 below summarizes the calculated mean exposure values ​​for acalabrutinib maleate tablets and the ratios of these calculated values ​​to the corresponding values ​​for acalabrutinib free base reference capsules. The exposure rate for T11 tablets was close to the lower limit of bioequivalence, which was likely due to a slower dissolution rate related to wettability issues.

[0150] [Table 9]

[0151] In a similar simulation, T10, T11, T13, and T15 tablets at 100 mg free base equivalent under neutral to acidic gastric conditions all exhibited the same mean AUC and C values ​​for acalabrutinib free base reference capsule C4 over the same pH range. max Mean AUC and C values ​​were substantially maintained across the pH range compared to max values. This simulation supported the conclusion that the effect of the reducing agent on acalabrutinib exposure may be substantially reduced compared to acalabrutinib free base reference capsules C4, with acalabrutinib maleate tablets maintaining bioequivalence across the acidic to neutral pH range. Table 10 below summarizes the calculated mean exposure values ​​for acalabrutinib maleate tablets and the ratios of these calculated values ​​to the corresponding values ​​for acalabrutinib free base reference capsules.

[0152] [Table 10]

[0153] Example 9: In vivo studies An in vivo study was conducted to evaluate the co-administration of acalabrutinib maleate and omeprazole compared to the co-administration of acalabrutinib free base and omeprazole in a canine model. During the study, previously treated beagle dogs were administered capsules containing 100 mg of acalabrutinib free base, both with and without prior treatment with 10 mg of omeprazole, and the AUC (0-24) Additionally, the same dogs, after an appropriate washout period, were administered a size 13 capsule containing a binary mixture of acalabrutinib maleate (100 mg equivalent) and 200 mg microcrystalline cellulose, both with and without omeprazole pretreatment, and the AUC (0-24) The results are shown in Figure 25. Acalabrutinib maleate capsules (100 mg free base equivalent) administered with omeprazole pretreatment maintained exposure comparable to acalabrutinib free base capsules administered without omeprazole pretreatment.

[0154] Example 10: Evaluation of excipients and excipient combinations Studies were conducted to assess the suitability of certain excipients and excipient combinations in formulating acalabrutinib maleate dosage forms.

[0155] A. Disintegrants Binary blends of disintegrant and acalabrutinib maleate (1:5 ratio) were prepared and evaluated in vitro in a dissolution test. Using a USP2 dissolution apparatus (paddle) at 37 ± 0.5 °C and 75 RPM, the binary blend and acalabrutinib maleate control were dissolved in 250 mL of deionized water. After 120 minutes, the paddle speed was increased to 250 RPM, and the pH was adjusted to 1.8-2 after 135 minutes to determine if any undissolved material remained and to increase solubility. The binary blends tested were sodium starch glycolate / acalabrutinib maleate (1:5 ratio), croscarmellose sodium / acalabrutinib maleate (1:5 ratio), and low-substituted hydroxypropyl cellulose / acalabrutinib maleate (1:5 ratio).

[0156] The results are shown in Figure 26. Only the acalabrutinib maleate control and the low-substituted hydroxypropyl cellulose / acalabrutinib maleate (1:5 ratio) mixture showed no significant increase in dissolution after increasing the paddle speed or adding acid, suggesting that complete dissolution was achieved. The croscarmellose sodium / acalabrutinib maleate (1:5 ratio) mixture and the croscarmellose sodium / acalabrutinib maleate (1:5 ratio) mixture showed a significant increase in dissolution when acid was added, indicating that complete release may be an issue at higher pH levels and possibly suggesting an excipient / drug substance interaction caused by conversion of acalabrutinib maleate to a less soluble form such as the free base.

[0157] B. Lubricant Binary mixtures (1:15) of disintegrant and acalabrutinib maleate were prepared and evaluated in vitro under the same conditions as described above for the disintegrant mixtures. The binary mixtures tested were glyceryl dibehenate / acalabrutinib maleate (1:15), magnesium stearate / acalabrutinib maleate (1:15), and sodium stearyl fumarate / acalabrutinib maleate (1:15).

[0158] The results are shown in Figure 27. The acalabrutinib maleate control, glyceryl dibehenate / acalabrutinib maleate (1:15) mixture, and sodium stearyl fumarate / acalabrutinib maleate (1:15) mixture showed no significant increase in dissolution after increasing the paddle speed or adding acid, suggesting that complete dissolution was achieved. For the magnesium stearate / acalabrutinib maleate (1:15) mixture, a significant increase in dissolution was observed when increasing the paddle speed and adjusting the acid, indicating that complete release may be an issue at higher pH levels and possibly suggesting an excipient / drug substance interaction caused by conversion of acalabrutinib maleate to a less soluble form such as the free base. Additionally, when two-component compacts of magnesium stearate and acalabrutinib maleate were evaluated, it was shown that the two-component compacts increased the degree of disintegration of acalabrutinib compared to acalabrutinib maleate alone.

[0159] C. Diluents Direct compression tablet cores containing diluents, disintegrants, lubricants, and acalabrutinib maleate were prepared and evaluated in vitro under the same conditions described above for the disintegrant mixtures. Each tablet core contained either microcrystalline cellulose / mannitol or microcrystalline cellulose / anhydrous calcium hydrogen phosphate / mannitol as the diluent. The specific tablet cores tested were: (1) microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol, low-substituted hydroxypropyl cellulose, magnesium stearate, and acalabrutinib maleate (T2); (2) microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, magnesium stearate, and acalabrutinib maleate (T3); (3) microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, and acalabrutinib maleate (T4). (4) microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, and acalabrutinib maleate (T6); (5) microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol, low-substituted hydroxypropyl cellulose, glyceryl dibehenate, and acalabrutinib maleate (T4); or (6) microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, glyceryl dibehenate, and acalabrutinib maleate (T5).

[0160] The results are shown in Figure 28 (tablet cores T2 and T3), Figure 29 (tablet cores T6 and T8), and Figure 30 (tablet cores T4 and T5). For all mixtures tested, the presence of anhydrous calcium hydrogen phosphate resulted in a greater increase in dissolution upon acid adjustment, suggesting an interaction between anhydrous calcium hydrogen phosphate and acalabrutinib maleate. In contrast, no significant increase was observed in mixtures without anhydrous calcium hydrogen phosphate. Additionally, when two-component compacts of anhydrous calcium hydrogen phosphate and acalabrutinib maleate were evaluated, the two-component compacts showed an increased degree of disintegration of acalabrutinib compared to acalabrutinib maleate alone.

[0161] Example 11: Evaluation of the stability of acalabrutinib maleate tablets A. Stability of Tablet T19 A stability study was conducted to evaluate acalabrutinib maleate tablets (T19) when presented in the following three packs under outdoor storage conditions: Bulk pack: 4-ply, tear-away aluminum foil laminated bag - 185 x 280 mm (60 tablets per bag) HPDE Bottle - 110mL induction-sealed bottle with 1g silica gel desiccant canister (60 tablets per bottle) HPDE Bottle - 110mL induction-sealed bottle with 2g silica gel desiccant canister (60 tablets per bottle) The storage conditions investigated in the stability studies are detailed in Table 11 below.

[0162] [Table 11]

[0163] At 26 weeks, the following data were available: Description: There was no change in the physical appearance of any of the samples. Assay: No trends were observed in the assay data for any of the samples tested. ·Organic impurities: For samples stored in appropriate packaging (HDPE bottles with desiccant or aluminum bulk bags), impurity levels met specification limits of 0.7% or less for permitted impurities and 0.2% or less for unpermitted impurities. Storage at 40°C / 75% RH for 4 weeks resulted in levels of 4-{2-[(2S)-1-(2-butynoyl)-2-pyrrolidinyl]-5-carbamimidoyl-1H-imidazol-4-yl}-N-(2-pyridinyl)benzamide exceeding the specification limit of 0.2% or less. All other impurities met the specification limits of 0.7% or less for permitted impurities and 0.2% or less for unpermitted impurities. Enantiomeric purity: All samples met method criteria at the initial and 26-week time points (≥99.6%). Dissolution (0.1N HCl): No trend was observed in any of the samples. All samples met the specification (Q = 80% at 20 minutes). Dissolution (pH 6.8): No trend was observed in any of the samples. All samples met Q=80% in 20 minutes. Moisture content: No trends were observed for samples stored with desiccants or in bulk packs. All field-stored samples showed an increase in moisture content over the four weeks, with the 40°C / 75%RH samples showing the greatest increase. Water activity: No trend was observed in the results. Microbiological properties: All results were in accordance with specifications (Pharm Eur / USP).

[0164] Based on the data generated, aluminum bulk bags were deemed appropriate to ensure adequate bulk holding time, and HDPE bottles with desiccants were deemed appropriate to ensure adequate shelf life for the acalabrutinib maleate film-coated tablets tested.

[0165] B. Additional Stability Assessment Stability studies were performed to assess the chemical stability of acalabrutinib maleate tablets T2 and T3, with the following general findings: The presence of anhydrous calcium hydrogen phosphate contributed to the formation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]-pyrazin-1-yl}-N-(2-pyridinyl)-benzamide and an RRT of 0.05. The presence of magnesium stearate contributed to the formation of 4-{2-[(2S)-1-(2-butynoyl)-2-pyrrolidinyl]-5-carbamimidoyl-1H-imidazol-4-yl}-N-(2-pyridinyl)-benzamide and an RRT of 0.82. The presence of microcrystalline cellulose contributed to the formation of 4-{3-[(2S)-1-acetoacetyl-2-pyrrolidinyl]-8-aminoimidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide, with an RRT of 0.82 and an RRT of 0.05.

[0166] Limited stability studies with limited data evaluation were performed on acalabrutinib maleate tablets T7 and T15, with the following findings: The main degradation products were 4-{3-[(2S)-1-acetoacetyl-2-pyrrolidinyl]-8-aminoimidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide, RRT 0.82, and 4-{2-[(2S)-1-(2-butynoyl)-2-pyrrolidinyl]-5-carbamimidoyl-1H-imidazol-4-yl}-N-(2-pyridinyl)-benzamide. The increase in 4-{3-[(2S)-1-acetoacetyl-2-pyrrolidinyl]-8-aminoimidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide levels and RRT0.82 was greater than that observed with acalabrutinib maleate tablets T2 and T3. Humidity appears to be a significant contributor to the formation of RRT0.82, but it is likely that this can be regulated by proper packaging.

[0167] Example 12: Preparation of acalabrutinib maleate A. Conversion of Acalabrutinib Free Base to Acalabrutinib Maleate [ka] Acalabrutinib (18 kg, 1.0 molar equivalent) in tetrahydrofuran (162 L, rel. volume 9.0) and water (9 L, rel. volume 0.5) was heated to 50°C and filtered. Tetrahydrofuran (9 L, rel. volume 0.5) was used as a line wash. Maleic acid (5 kg, 1.1 molar equivalent) in tetrahydrofuran (68 L, rel. volume 3.75) was added at 50°C, followed by a line wash of tetrahydrofuran (5 L, rel. volume 0.25). The mixture was seeded with acalabrutinib maleate (18 mg, rel. volume 0.001) and held at 50°C for 1 hour, then cooled to 20°C over 1 hour, held for 1 hour, and then wet-milled to obtain the desired particle size distribution. The product was then filtered and washed with tetrahydrofuran (36 L, relative volume 2.0) and then dried under a nitrogen stream (>20% relative humidity) at 40°C to give acalabrutinib maleate (20.4 kg, 88%) as the monohydrate.

[0168] B. Conversion of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)-benzamide to acalabrutinib maleate [ka] In an alternative method for preparing acalabrutinib maleate, the maleate salt was prepared without isolation of acalabrutinib free base. To a mixture of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)-benzamide (15.0 g, 1.0 molar equivalent) and triethylamine (13.2 mL, 2.6 molar equivalents) in tetrahydrofuran (80 mL, 5.3 relative volume) was added (over 1 hour) 2-butynoic acid (3.3 g, 1.1 molar equivalents) in tetrahydrofuran (15 mL, 1.0 relative volume), followed after 8 minutes by the addition of propylphosphonic anhydride (53% w / w in ethyl acetate) (23.7 g, 1.1 molar equivalents) in tetrahydrofuran (15 mL, 1.0 relative volume), both of which were added (over 1 hour). The mixture was stirred until the reaction was complete. The mixture was quenched with water (30 mL, rel. volume 2.0), and the aqueous phase was separated and discarded. The remaining organic phase was filtered with a line wash of tetrahydrofuran (7 mL, rel. volume 0.5). The mixture was then heated to 50°C and treated with maleic acid (8 g, 1.9 molar equivalents) in tetrahydrofuran (59 mL, rel. volume 3.9). The mixture was seeded with acalabrutinib maleate (15 mg, rel. volume 0.001), then cooled to 20°C over 5 hours, filtered, washed three times with ethanol (30 mL, rel. volume 2.0), then with tert-butyl methyl ether (58 mL, rel. volume 3.9), and then blotted on the filter for 30 minutes to yield acalabrutinib maleate (16 g, 74%) as the monohydrate.

[0169] Analysis of the product from Method B above showed the presence of an impurity, (2Z)-4-[(2S)-2-{8-amino-1-[4-(2-pyridinylcarbamoyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}-1-pyrrolidinyl]-4-oxo-2-butenoic acid, which was not observed in the product from Method A. This impurity was present in an amount that required toxicological qualification of the impurity for regulatory registration of acalabrutinib maleate tablets formulated with the drug substance prepared by Method B.

[0170] Example 13: Preparation of acalabrutinib maleate tablets Figure 31 shows a schematic overview of the process for preparing acalabrutinib maleate tablet T21 of Example 4. Specifically, acalabrutinib maleate, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose are added to a suitable diffusion mixer and mixed together. The intragranular portion of sodium stearyl fumarate is added to the powder and mixed before roller compaction. Ribbons are produced by roller compacting the lubricated blend. The ribbons are then broken into granules by passing them through a suitable mill. The granules are mixed with the extragranular portion of sodium stearyl fumarate using a suitable diffusion mixer. The lubricated granules are compressed into tablet cores using a suitable tablet press. An orange film-coated suspension was prepared and applied to the tablet cores using a conventional film-coating process.

[0171] Example 14: Relative bioavailability studies A phase 1, open-label, single-dose, sequential, randomized study of acalabrutinib maleate tablets was conducted in healthy human subjects to evaluate relative bioavailability, the effect of a proton pump inhibitor (rabeprazole), the effect of food, and the effect of particle size. The study is divided into two parts. Part 1 is intended to test the relative bioavailability of acalabrutinib maleate tablets versus acalabrutinib free base capsules as a pilot study to inform the design of Part 2. Part 1 also is intended to test the effect of a proton pump inhibitor ("PPI") and the effect of food on exposure to acalabrutinib maleate tablets. After review of the safety and pharmacokinetic data from Part 1, the study will continue into Part 2. Study Part 2 is intended to examine the effect of changes in particle size of the drug substance when exposed to acalabrutinib maleate tablets and the relative bioavailability of acalabrutinib maleate tablets versus solution. The results of this study will provide information on the pharmacokinetic and pharmacodynamic profiles of acalabrutinib maleate tablets to be evaluated.

[0172] A. Study Design Part 1 Exam Objectives Main purpose: To assess the relative bioavailability of acalabrutinib maleate tablets compared with acalabrutinib free base capsules in fasted subjects.

[0173] Secondary Objectives: To evaluate the pharmacokinetic profile of acalabrutinib maleate tablets (ACP-5862) compared to acalabrutinib free base capsules under fasting conditions. To evaluate the effect of the proton pump inhibitor, rabeprazole, on the pharmacokinetic profiles of acalabrutinib and its metabolite (ACP-5862) after administration of acalabrutinib maleate tablets. To assess the effect of food on the pharmacokinetics of acalabrutinib and its metabolite (ACP-5862) obtained after administration of acalabrutinib maleate tablets. To assess the safety and tolerability of a single dose of acalabrutinib maleate tablets in healthy subjects. To measure BTK receptor occupancy, a pharmacodynamic parameter, for acalabrutinib maleate tablets and acalabrutinib free base capsules in isolated PBMCs.

[0174] Exploratory purpose: To assess differences in exposure by H pylori breath test status (present / absent). Collecting pH information for smart pills and using this information as input into the PBPK model to calculate individual in vivo dissolution.

[0175] Part 2 Exam Objectives Main purpose: To assess the effect of drug substance particle size on the bioavailability of acalabrutinib maleate tablets.

[0176] Secondary Objectives: To evaluate the effect of drug substance particle size on the pharmacokinetic profile of ACP-5862 in acalabrutinib maleate tablets. To compare the pharmacokinetics of acalabrutinib maleate tablets and acalabrutinib oral solution in healthy subjects. To evaluate the safety and tolerability of single-dose acalabrutinib maleate tablets with different drug substance particle size distributions in healthy subjects. To evaluate the safety, tolerability, taste, and odor of a single dose of acalabrutinib oral solution in healthy subjects.

[0177] Part 1 Study Design: Part 1 of the study is an open-label, three-treatment period, four-treatment, single-center, randomized crossover trial of novel acalabrutinib maleate tablets in healthy subjects (men or women of non-childbearing potential) to evaluate the relative bioavailability, effect of PPIs, and effect of food.

[0178] Part 1 of the exam consists of: - Maximum screening period of 28 days, Three treatment periods in which subjects reside before dinner the night before dosing (Day -1) until at least 48 hours after dosing and are discharged on the morning of Day 3; and · Follow-up visit within 7-10 days. There will be a minimum washout period of 7 days between each dose of acalabrutinib. Each subject will receive three of the following four treatments over three treatment periods under fasting or fed conditions: Subjects will be randomized to receive either Treatment A or B in Treatment Periods 1 and 2, followed by either Treatment C or D in Treatment Period 3. The 100 mg acalabrutinib maleate tablets (variant 1) contain active pharmaceutical ingredient with a D of 218 μm or less. (v,0.9) Tablet T21 (see Example 4, Table 7) has the composition of particle size. Treatment A: 100 mg acalabrutinib free base capsules, fasted (>10 hours) * . Treatment B: 100 mg acalabrutinib maleate tablets (variant 1), fasting (>10 hours) * . Treatment C: 100 mg acalabrutinib maleate tablet (variant 1) after meals *,** . Treatment D: On days -3, -2, and -1, rabeprazole 20 mg x 1 (on an empty stomach) was administered 2 hours before administration of a 100 mg acalabrutinib maleate tablet (variant 1). * , followed by premedication with rabeprazole 20 mg BID (with food). *Each subject will receive a SmartPill with 120 mL of still water immediately followed by a single oral dose of a Calquence maleate tablet (Treatment B, C, or D) or a Calquence free base capsule (Treatment A) with 120 mL of still water, followed by PK collection over 24 hours. ** Subjects will begin consuming a high-fat (FDA) meal 30 minutes prior to administration of the SmartPill / 100mg acalabrutinib maleate tablet. Subjects will be required to consume the meal within 25 minutes; however, the SmartPill / IMP must be administered 30 minutes after the start of the meal.

[0179] Part 2 Study Design: Part 2 of the study is an open-label, four-period, four-treatment, single-center, relative bioavailability, randomized crossover study to determine the effect of particle size on the PK of a single-dose acalabrutinib maleate tablet in healthy subjects (males or females of non-childbearing potential).

[0180] Part 2 of the exam consists of: - Maximum screening period of 28 days, 4 treatment periods in which subjects reside before dinner the night before dosing (Day -1) until at least 48 hours after dosing and are discharged on the morning of Day 3; and · Follow-up visit within 7-10 days.

[0181] There will be a minimum washout period of at least 3 days between each dose of acalabrutinib.

[0182] Each subject will receive the following treatment: Treatment A: 100 mg acalabrutinib maleate tablets (variant 1), taken on an empty stomach Treatment B: 100 mg acalabrutinib maleate tablets (variant 2), taken on an empty stomach Treatment C: 100 mg acalabrutinib maleate tablets (variant 3), fasting Treatment D: 100 mg of acalabrutinib solution, fasting

[0183] The 100 mg acalabrutinib maleate tablet (variant 1) contains a drug substance with an intermediate particle size, while the 100 mg acalabrutinib maleate tablet (variant 2) contains a drug substance with a smaller particle size, and the 100 mg acalabrutinib maleate tablet (variant 3) contains a drug substance with a larger particle size. Specifically, the 100 mg acalabrutinib maleate tablet has the composition of tablet T21 (see Example 4, Table 7), and variant 1 contains a drug substance with a D of 218 μm or less. (v,0.9) Variation 2 includes a drug substance having a particle size of 160 μm or less, D (v,0.9) Variation 3 includes a drug substance having a particle size of 319 μm or less, D (v,0.9) Contains a drug substance having a particle size.

[0184] Expected test duration In Part 1, each subject will be involved in the study for approximately 7-8 weeks. In Part 2, each subject will be involved in the study for approximately 6-7 weeks.

[0185] Target study population Part 1 of the study will include a total of 28 healthy male and female subjects aged 18-55 years (inclusive) to ensure at least 24 evaluable subjects. Part 2 of the study will include a total of 24 healthy male and female subjects aged 18-55 years (inclusive) to ensure 20 evaluable subjects at the end of the last treatment period.

[0186] Outcome evaluation items Pharmacokinetic endpoints: Serial venous blood samples will be obtained to measure plasma concentrations of acalabrutinib and its metabolite (ACP-5862). Where possible, pharmacokinetic parameters will be assessed for acalabrutinib and its metabolite ACP-5862 in plasma concentrations.

[0187] Parts 1 and 2: Primary PK parameter: C of acalabrutinib max , AUC last , AUC inf Secondary PK parameters: C of ACP-5862 max , AUC last , AUC inf ;Acalabrutinib and ACP-5862:AUC 0-12 , AUC last , AUC inf , %AUC extrap , C max , t 1 / 2 , t max ,Kel,F rel , CL / F (parent only), Vz / F (parent only), C max , AUC last , AUC inf Ratio of ACP-5862 (metabolite) to acalabrutinib (parent) (M / P). Additional PK parameters may be measured as needed.

[0188] Safety and tolerability endpoints: Safety and tolerability variables included the following: Adverse events / serious adverse events. · Clinical laboratory evaluation (hematology, clinical chemistry, coagulation and urinalysis). Physical examination. Electrocardiogram (12-lead ECG): · Vital signs (systolic and diastolic BP, pulse rate, respiratory rate, temperature). Taste and odor assessment (Part 2 only).

[0189] Exploratory Endpoints (Part 1): Calquence and ACP-5862: Repeated measures analysis of covariance (ANCOVA) was used to evaluate PK parameters (AUC last , AUC inf , and C max ) and assess differences in exposure due to gastric pH and gastric emptying rate using appropriate statistical procedures. Temperature, pH and pressure profiles throughout the gastrointestinal tract; gastric pH immediately after administration of the acalabrutinib product (first measurable time point) (Part 1 only) H pylori breath test status

[0190] Part 1 Statistical Methods: To assess the relative bioavailability of acalabrutinib maleate tablets compared to acalabrutinib free base capsules under fasted conditions, primary PK parameters of acalabrutinib and its metabolite ACP-5862 will be compared between Treatment B (acalabrutinib) and Treatment A (acalabrutinib free base capsules). max , AUC inf , and AUC last The analysis is performed using a linear mixed-effects analysis of variance model with the natural logarithm of as the response variable, sequence, period, and treatment as fixed effects, and volunteer nested within sequence as a random effect. inf , AUC last , and C max We will estimate and present the geometric means with CIs (two-sided 95%). We will also estimate and present the geometric mean ratios with CIs (two-sided 90%).

[0191] To evaluate the effect of the proton pump inhibitor, rabeprazole, on the PK profiles of acalabrutinib and its metabolite (ACP-5862) obtained after administration of acalabrutinib maleate tablets, the primary PK parameters of acalabrutinib and its metabolite, ACP-5862, are compared between Treatment D (rabeprazole) and Treatment B (acalabrutinib) using the same analysis of variance (ANOVA) model.

[0192] To assess the effect of food on the PK of acalabrutinib and its metabolite (ACP-5862) following administration of acalabrutinib maleate tablets, the primary PK parameters of acalabrutinib and its metabolite, ACP-5862, are compared between Treatment C (fed) and Treatment B (fasted) using the same ANOVA model.

[0193] Part 2 Statistical Methods To assess the effect of particle size of the drug substance on the bioavailability of acalabrutinib maleate tablets, the primary PK parameters of acalabrutinib and its metabolite, ACP-5862, were compared between Treatment B (smaller than target) and Treatment A (on target), Treatment C (larger than target) and Treatment A (on target), and Treatment C (larger than target) and Treatment B (smaller than target). max , AUC inf , and AUC last The analysis is performed using a linear mixed-effects analysis of variance model with the natural logarithm of as the response variable, sequence, period, and treatment as fixed effects, and volunteer nested within sequence as a random effect. inf , AUC last , and C max We will estimate and present the geometric means with CIs (two-sided 95%). We will also estimate and present the geometric mean ratios with CIs (two-sided 90%).

[0194] To compare the PK of acalabrutinib maleate tablets and acalabrutinib oral solution, the primary PK parameters of acalabrutinib and its metabolite, ACP-5862, will be compared between Treatment D (solution) and Treatment A (target) using the same ANOVA model.

[0195] Part 1 and Part 2 Statistical Methods: Additionally, the 90% CI for the difference in mean tmax using the same comparisons by ANOVA will be calculated and presented. Mean differences and 90% confidence intervals will be tabulated for each comparison and analysis.

[0196] Results are expected to demonstrate that co-administration of a PPI or other reducing agent with acalabrutinib maleate tablets does not affect the exposure of acalabrutinib and ACP-5862.

[0197] B. Test Results Pharmacokinetics The results of Part 1 of the study showed that acalabrutinib maleate tablets (variant 1) and acalabrutinib capsules had similar bioavailability. Mean pharmacokinetic exposure (C) of acalabrutinib and its metabolite ACP-5862 max and AUC) were similar after fasting administration of acalabrutinib maleate tablets (variant 1) and acalabrutinib capsules. Relative bioavailability was also observed for acalabrutinib C max and AUC were approximately 91% and 98%, respectively, and the C of ACP-5862 max and AUC were approximately 100% and 103% to 104%, respectively. Co-administration of PPI (rabeprazole) with acalabrutinib maleate tablets (variant 1) had no apparent effect on the pharmacokinetic exposure of acalabrutinib and its metabolite ACP-5862. max The C of ACP-5862 was slightly lower (approximately 24% difference in geometric mean) and the AUC was slightly higher (approximately 14-17% difference in geometric mean). max was approximately 30% lower and comparable to the AUC in the presence and absence of a PPI. In the case of acalabrutinib maleate tablets (variant 1), the C of acalabrutinib and ACP-5862 is determined by food. max were decreased by approximately 54% and 36%, respectively, without affecting the overall AUC. There was no difference in BTK occupancy across treatments, resulting in a significant difference in C for acalabrutinib and ACP-5862. max The inter-subject variability (geometric CV%) in max Differences in are unlikely to have a clinically meaningful effect.

[0198] A summary of the plasma pharmacokinetic parameters from Part 1 of the study is shown in Tables 12-16 below.

[0199] [Table 12]

[0200] [Table 13]

[0201] [Table 14]

[0202] [Table 15]

[0203] [Table 16]

[0204] Results from Part 2 of the study demonstrated that particle size of acalabrutinib maleate did not significantly affect the pharmacokinetics of acalabrutinib and ACP-5862 across the particle size range evaluated. Following administration, variants 1, 2, and 3 all resulted in equivalent pharmacokinetic exposure. Mean pharmacokinetic exposure (C) of acalabrutinib and its metabolite ACP-5862 max and AUC) were similar after oral administration of acalabrutinib maleate tablets with different particle sizes (variants 1, 2, and 3). The 90% CIs of the geometric mean ratios were approximately or well within the 80% to 125% margin. Acalabrutinib solution has a higher C value compared to acalabrutinib maleate tablets (variant 1). max The relative bioavailability was comparable to that of acalabrutinib. max and AUC were approximately 122% and 102%, respectively, and the C of ACP-5862 max and AUC were approximately 124% and 106% to 107%, respectively.

[0205] A summary of the plasma pharmacokinetic parameters from Part 2 of the study is shown in Tables 17-21.

[0206] [Table 17]

[0207] [Table 18]

[0208] [Table 19]

[0209] [Table 20]

[0210] [Table 21]

[0211] Pharmacodynamics Part 1 of the study investigated BTK receptor occupancy with acalabrutinib when administered as a capsule or tablet. Results showed that BTK occupancy was similar after administration of the tablet and capsule formulations across all time points post-dose (4, 12, and 24 hours). Additionally, BTK occupancy for the tablet formulation was not affected by food or PPI administration.

[0212] search Gastric pH was found to have no effect on the exposure of acalabrutinib maleate from 100 mg acalabrutinib maleate film-coated tablets and therefore the in vivo dissolution of the tablets was not sensitive to gastric pH.

[0213] safety Overall, no new safety concerns were observed with the 100 mg acalabrutinib maleate film-coated tablets, and the new formulation was well tolerated.

[0214] Example 15: Bioequivalence Evaluation An open-label, randomized, two-period crossover bioequivalence study was conducted in healthy subjects to evaluate the bioequivalence of acalabrutinib maleate tablets (test formulation) and acalabrutinib free base capsules (reference formulation).The study is intended to demonstrate the bioequivalence of acalabrutinib maleate tablets and acalabrutinib free base capsules in accordance with regulatory requirements.

[0215] Exam Title: A Phase 1, open-label, randomized, two-treatment, two-period, crossover study in healthy subjects to evaluate the bioequivalence of acalabrutinib tablets and acalabrutinib capsules.

[0216] Test rationale: Acalabrutinib is a Biopharmaceutics Classification System (BCS) Class II drug (highly permeable, low solubility) and exhibits a base dissociation constant of 2 in the physiological pH range. Acalabrutinib solubility decreases as pH increases. At pH below 4, the drug is highly soluble. However, in patients taking acid-reducing agents (i.e., at pH above 4), the drug's solubility in the stomach / intestine is insufficient to ensure complete dissolution and absorption of the drug. Findings from a Phase I study (Study ACE-HV-112) have shown that administration of 100 mg acalabrutinib capsules after 40 mg omeprazole (a proton pump inhibitor (PPI)) once daily (qd) resulted in a 43% decrease in AUC and C compared to administration of the drug under normal acidic pH conditions. max was shown to reduce by 72%.

[0217] At the administration of a 100 mg equivalent free fraction, acalabrutinib maleate tablets (AMT) demonstrate pH-dependent release in vitro, in contrast to acalabrutinib capsules (i.e., Calquence). Results of a relative bioavailability study (see Example 14) demonstrated that the systemic exposure of acalabrutinib and its active metabolite, ACP-5862, following administration of AMT was similar in the presence or absence of a PPI and equivalent to the systemic exposure observed with 100 mg acalabrutinib capsules. This bioequivalence study is intended to confirm that 100 mg AMT eliminates the effect of PPIs on the pharmacokinetics (PK) of acalabrutinib in humans.

[0218] Planned target population Approximately 64 subjects (approximately 32 per treatment sequence) will be randomized to ensure at least 52 evaluable subjects (26 per sequence) at the end of Treatment Period 2.

[0219] Test Purpose Main purpose: To demonstrate the bioequivalence of AMT and acalabrutinib capsules administered in the fasted state.

[0220] Secondary Objectives: To compare the pharmacokinetic profiles of ACP-5862, the active metabolite of acalabrutinib, after administration of AMT and acalabrutinib capsules. To assess the safety and tolerability of single-dose AMT and acalabrutinib capsules.

[0221] Exploratory purpose: To determine the pharmacodynamics (PD) of acalabrutinib.

[0222] Study design This is a multicenter, Phase 1, open-label, randomized, two-sequence, two-treatment, two-period, crossover, bioequivalence study of a single dose of acalabrutinib administered orally to healthy subjects at approximately three study sites in the U.S. The study is designed to demonstrate the bioequivalence of AMT (Treatment A) compared to the marketed acalabrutinib capsule formulation (Treatment B) under fasting conditions.

[0223] The test consists of: Visit 1: Screening period up to 28 days after first dose. 2 visits: 2 treatment periods: Subjects will be admitted to the study site on Day -2 of Treatment Period 1 to confirm eligibility prior to the first dose. Eligibility criteria will be confirmed on Day -1 of each treatment period. On Day 1 of Treatment Periods 1 and 2, subjects will receive the randomly assigned treatment (A or B), followed by a washout period of at least 5 days between Treatment Periods 1 and 2. After scheduled study assessments are completed, subjects will be discharged from the study site on the morning of Day 3 of Treatment Period 2. Visit 3: Follow-up visit / early discontinuation visit 7-10 days after the last dose of IMP.

[0224] For follow-up / early discontinuation visits, telehealth visits may replace on-site visits or portions thereof, if necessary (laboratory tests, ECG, and tympanic temperature will not be performed when a telehealth visit is conducted). The term telehealth visit refers to a virtual or video visit. During public health crises such as civil war, natural disaster, or the COVID-19 pandemic, on-site visits may be replaced with telehealth visits if permitted by local / regional guidelines. Contacting subjects via telehealth allows for reporting and documentation of adverse events (AEs) and concomitant medications, which should be collected according to study requirements.

[0225] Subjects will be randomized to receive either Treatment Sequence 1 (AB) or Treatment Sequence 2 (BA). AMT is defined as a treatment in which the drug substance has a D of 218 μm or less. (v,0.9)Tablet T21 (see Example 4, Table 7) has the composition of particle size. ·Treatment A: AMT, 100mg, fasting. Treatment B: Acalabrutinib capsules, 100 mg, on an empty stomach. Subjects will receive a single fixed dose of acalabrutinib on two occasions under fasting conditions.

[0226] Expected test duration Each subject will be involved in the study for approximately 6 weeks.

[0227] Target study population Healthy adult male and female subjects aged 18-55 years (inclusive), with a BMI of 18.5-30 kg / m2 (inclusive), who are non-smokers, and women must not be of childbearing potential.

[0228] Test and reference products

[0229] [Table 22]

[0230] Outcome evaluation items Safety and tolerability endpoints: Adverse events. · Clinical laboratory evaluation (hematology, coagulation, clinical chemistry, and urinalysis). Physical examination. ·Electrocardiogram (ECG). · Vital signs (systolic blood pressure [BP], diastolic BP, pulse, respiratory rate, tympanic membrane, temperature).

[0231] Pharmacokinetic endpoints: Primary PK parameters: Acalabrutinib-AUC inf , AUC last , C max

[0232] Secondary PK parameters: Acalabrutinib-tmax , t 1 / 2 λz, MRT, λz, CL / F, Vz / F ACP-5862-AUC inf , AUC last , C max , t max , t 1 / 2 λz, MRT, λz, M:P[AUC], M:P[C max ]

[0233] statistical methods All statistical analyses and preparation of tables, figures and listings will be performed using SAS® version 9.4 or more recent versions.

[0234] Analysis data population: The safety analysis set includes all subjects who received at least one dose in Treatment Period 1 and for whom safety data after any dose are available. The PK analysis set consists of all subjects in the safety analysis set with at least one quantifiable post-dose acalabrutinib concentration without a significant protocol deviation or adverse event considered to affect the analysis of PK data. The randomized set consists of all subjects randomized into the study.

[0235] Presentation and analysis of safety and tolerability data: All safety data (scheduled and unscheduled) will be presented in data listings. Continuous variables will be summarized by treatment using descriptive statistics (number of subjects [n], mean, standard deviation [SD], minimum, median, maximum). Categorical variables will be summarized in frequency tables (frequencies and percentages) by treatment. Analysis of safety variables will be based on the safety analysis set.

[0236] Adverse events will be summarized by system organ class (SOC) and preferred term using the latest revision of the Medical Dictionary for Regulatory Affairs (MedDRA) vocabulary. Data tabulation and listing will be presented for vital signs, laboratory tests, and ECG. Any new or worsening clinically significant abnormal medical physical examination finding compared to the baseline assessment will be reported as an adverse event. Laboratory data will be reported in units provided by the clinical laboratory or in the International System of Units.

[0237] Pharmacokinetic data presentation: A listing of PK blood sample collection times and derived collection lags will be provided. For each analyte, plasma concentrations and PK parameters will be tabulated by treatment. Diagnostic PK parameters will be tabulated and listed. Tabulations will be based on the PK population. Data for subjects excluded from the PK population will be included in the data listing but not in the descriptive or inferential statistics. For each analyte, individual plasma concentrations will be plotted against real time on linear and semi-log scales, with all treatments superimposed on the same plot and on separate plots for each subject. Combined individual plasma concentrations against real time will be plotted on linear and semi-log scales, with separate plots for each treatment and analyte. Geometric mean plasma concentrations against nominal collection times will be plotted on linear scale (- / + geometric SD) and semi-log scale (geometric SD not shown), with all treatments superimposed on the same plot and on separate plots for each analyte. All plots will be based on the PK population, except for individual plots by subject, which will be based on the safety population.

[0238] Statistical analysis of pharmacokinetic data: Bioequivalence will be assessed between Treatment A: AMT (study) and Treatment B: acalabrutinib capsules (standard) based on the PK analysis population. Sequence, period, and treatment will be used as fixed effects, and subjects nested within sequences will be used as random effects. max , AUC last , and AUC inf The analysis is carried out using a linear mixed-effects analysis of variance model with the natural logarithm of as the response variable.max , AUC last , and AUC inf The geometric means of the CIs are estimated and presented with confidence intervals (CI) (two-sided 95%). The geometric mean ratios are estimated and presented with CIs (two-sided 90%). In addition, the inter-%CV and intra-%CV are calculated for the C of acalabrutinib and ACP-5862. max , AUC inf , AUC last We will estimate and present each of these.

[0239] Bioequivalence criteria: C between tests and standards max and AUC last or AUC inf If the 90% CI of the log-transformed geometric mean ratio of is completely contained within the range of 80.00% and 125.00%, it will be concluded that the two treatments are bioequivalent. Statistical analysis to demonstrate bioequivalence will be performed by combining PK data across all study sites.

[0240] Pharmacodynamic data presentation and analysis: Results of exploratory PD parameters (BTK receptor occupancy) will be listed and summarized as necessary based on the pharmacokinetic analysis population.

[0241] Determining the number of cases: Acalabrutinib C max and AUC inf Bioequivalence ranges from 80.00% to 125.00%. max 29.8%, AUC inf Based on a within-subject CV of 15.1% (Study ACE-HV-115) and a mean "test / standard" ratio of 0.95, 52 evaluable subjects would be required to achieve 90% power.

[0242] Overall, each C max and AUC inf A total of 64 subjects will provide at least 95% power to conclude bioequivalence for each of the 200 mg / kg bw and 200 mg / kg bw.

[0243] VIII. Embodiments Embodiment 1: A solid pharmaceutical dosage form for oral administration to humans, comprising about 75 mg to about 125 mg (free base equivalent) of acalabrutinib maleate and at least one pharmaceutically acceptable excipient, wherein the dosage form meets the following conditions: (i) at least about 75% of the acalabrutinib maleate dissolves within about 30 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and (ii) at least about 75% of the acalabrutinib maleate dissolves within about 60 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM.

[0244] Embodiment 2: The dosage form of embodiment 1, wherein the dosage form satisfies the following conditions: (i) at least about 75% of the acalabrutinib maleate dissolves within about 20 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and (ii) at least about 75% of the acalabrutinib maleate dissolves within about 45 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM.

[0245] Embodiment 3: The dosage form of embodiment 1, wherein the dosage form satisfies the following conditions: (i) at least about 80% of the acalabrutinib maleate dissolves within about 20 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and (ii) at least about 80% of the acalabrutinib maleate dissolves within about 30 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM.

[0246] Embodiment 4: The dosage form of embodiment 1, wherein the dosage form satisfies the following conditions: (i) at least about 80% of the acalabrutinib maleate dissolves within about 15 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and (ii) at least about 80% of the acalabrutinib maleate dissolves within about 20 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM.

[0247] Embodiment 5: A dosage form of any one of embodiments 1 to 4, wherein the acalabrutinib maleate is acalabrutinib maleate monohydrate.

[0248] Embodiment 6: The dosage form of embodiment 5, wherein the acalabrutinib maleate monohydrate is crystalline form A.

[0249] Embodiment 7: The dosage form of any of embodiments 1-6, wherein the at least one pharmaceutically acceptable excipient is selected from at least one diluent, at least one disintegrant, and at least one lubricant.

[0250] Embodiment 8: A dosage form of any of embodiments 1 to 7, wherein the dissolution rate of acalabrutinib maleate in 5 mM phosphate pH 6.8 dissolution medium does not decrease by more than 20% from its initial dissolution rate after storage of the dosage form in suitable packaging at 40°C and 75% relative humidity for 6 months.

[0251] Embodiment 9: A dosage form of any of embodiments 1 to 7, wherein the dissolution rate of acalabrutinib maleate in 5 mM phosphate pH 6.8 dissolution medium does not decrease by more than 10% from its initial dissolution rate after storage of the dosage form in suitable packaging at 40°C and 75% relative humidity for 6 months.

[0252] Embodiment 10: A dosage form of any of embodiments 1 to 7, wherein the dissolution rate of acalabrutinib maleate in 5 mM phosphate pH 6.8 dissolution medium does not decrease by more than 5% from its initial dissolution rate after storage of the dosage form in suitable packaging at 40°C and 75% relative humidity for 6 months.

[0253] Embodiment 11: A dosage form of any of embodiments 1 to 7, wherein the dissolution rate of acalabrutinib maleate in 5 mM phosphate pH 6.8 dissolution medium does not decrease by more than 2% from its initial dissolution rate after storage of the dosage form in suitable packaging at 40°C and 75% relative humidity for 6 months.

[0254] Embodiment 12: A dosage form of any one of embodiments 1 to 11, wherein no more than about 5% (w / w) of the acalabrutinib maleate present in the dosage form is degraded after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months.

[0255] Embodiment 13: A dosage form of any one of embodiments 1 to 11, wherein no more than about 2% (w / w) of the acalabrutinib maleate present in the dosage form is degraded after storage of the dosage form in suitable packaging at 40°C and 75% relative humidity for 6 months.

[0256] Embodiment 14: A dosage form of any one of embodiments 1 to 11, wherein no more than about 1% (w / w) of the acalabrutinib maleate present in the dosage form is degraded after the dosage form is stored in suitable packaging at 40°C and 75% relative humidity for 6 months.

[0257] Embodiment 15: A dosage form of any one of embodiments 1 to 11, wherein no more than about 0.5% (w / w) of the acalabrutinib maleate present in the dosage form is degraded after storage of the dosage form in suitable packaging at 40°C and 75% relative humidity for 6 months.

[0258] Embodiment 16: A dosage form of any of embodiments 1-15, wherein the dosage form is bioequivalent to 100 mg Calquence® capsules when orally administered to fasted human subjects not receiving a gastric acid reducing agent, wherein the confidence intervals for the relative mean Cmax, AUC(0-t), and AUC(0-∞) of the dosage form to 100 mg Calquence® capsules are within the ranges of 80% to 125%.

[0259] Embodiment 17: The dosage form of any of embodiments 1-15, wherein the dosage form, when administered twice daily to a population of fasted human subjects, satisfies one or more of the pharmacokinetic conditions of acalabrutinib: (i) a mean Cmax value in the population of human subjects of from about 400 ng / mL to about 900 ng / mL; (ii) a mean AUC(0-24) value in the population of human subjects of from about 350 ng hr / mL to about 1900 ng hr / mL; and / or (iii) a mean AUC(0-∞) value in the population of human subjects of from about 350 ng hr / mL to about 1900 ng hr / mL.

[0260] Embodiment 18: The dosage form of embodiment 17, wherein the dosage form is co-administered with a gastric acid reducing agent to a population of human subjects.

[0261] Embodiment 19: The dosage form of any of embodiments 1-18, wherein the dosage form provides a median steady-state Bruton's tyrosine kinase occupancy in peripheral blood mononuclear cells of at least about 90% when administered twice daily to a human subject.

[0262] Embodiment 20: The dosage form of any of embodiments 1-18, wherein the dosage form provides a median steady-state Bruton's tyrosine kinase occupancy in peripheral blood mononuclear cells of at least about 95% when administered twice daily to a human subject.

[0263] Embodiment 21: The dosage form of embodiment 19 or 20, wherein the dosage form is co-administered with a gastric acid reducing agent to a population of human subjects.

[0264] Embodiment 22: A dosage form of any of embodiments 1-21, wherein acalabrutinib maleate is present in an amount of about 15% to about 55% (free base equivalent) by weight of the dosage form.

[0265] Embodiment 23: A dosage form of any of embodiments 1-21, wherein acalabrutinib maleate is present in an amount of about 20% to about 50% (free base equivalent) by weight of the dosage form.

[0266] Embodiment 24: A dosage form of any of embodiments 1-21, wherein acalabrutinib maleate is present in an amount of about 25% to about 50% (free base equivalent) by weight of the dosage form.

[0267] Embodiment 25: A dosage form of any of embodiments 1-21, wherein acalabrutinib maleate is present in an amount of about 25% to about 40% (free base equivalent) by weight of the dosage form.

[0268] Embodiment 26: The dosage form of any of embodiments 1 to 25, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent.

[0269] Embodiment 27: The dosage form of embodiment 26, wherein the at least one diluent is present in an amount of about 10% to about 70% by weight of the dosage form.

[0270] Embodiment 28: The dosage form of embodiment 26, wherein the at least one diluent is present in an amount of about 20% to about 70% by weight of the dosage form.

[0271] Embodiment 29: The dosage form of embodiment 26, wherein the at least one diluent is present in an amount of about 30% to about 70% by weight of the dosage form.

[0272] Embodiment 30: The dosage form of embodiment 26, wherein the at least one diluent is present in an amount of about 40% to about 70% by weight of the dosage form.

[0273] Embodiment 31: A dosage form of any of embodiments 26 to 30, wherein at least one diluent does not affect the stability of the primary amine moiety of acalabrutinib.

[0274] Embodiment 32: A dosage form according to any one of embodiments 26 to 30, wherein at least one diluent does not contain lactose.

[0275] Embodiment 33: The dosage form of any of embodiments 26-32, wherein at least one diluent does not comprise a maleic acid scavenger.

[0276] Embodiment 34: A dosage form according to any one of embodiments 26 to 33, wherein at least one diluent does not comprise anhydrous calcium hydrogen phosphate.

[0277] Embodiment 35: A dosage form according to any one of embodiments 26 to 34, wherein the at least one diluent comprises a plastic diluent and a brittle diluent.

[0278] Embodiment 36: The dosage form of embodiment 35, wherein the w / w ratio of plastic diluent to brittle diluent is from about 0:100 to about 60:40.

[0279] Embodiment 37: The dosage form of embodiment 35 or 36, wherein (i) the one or more diluents comprise a plastic diluent and a brittle diluent in a total amount of about 10% to about 70% by weight of the dosage form, (ii) the plastic diluent is present in an amount of about 0% to about 70% by weight of the dosage form, and (iii) the brittle diluent is present in an amount of about 0% to about 50% by weight of the dosage form.

[0280] Embodiment 38: A dosage form according to any of embodiments 26 to 34, wherein at least one diluent comprises mannitol.

[0281] Embodiment 39: A dosage form according to any one of embodiments 26 to 34, wherein at least one diluent comprises microcrystalline cellulose.

[0282] Embodiment 40: A dosage form according to any of embodiments 26 to 34, wherein the at least one diluent comprises mannitol and microcrystalline cellulose.

[0283] Embodiment 41: A dosage form according to embodiment 40, wherein the w / w ratio of mannitol to microcrystalline cellulose is from about 0:100 to about 60:40.

[0284] Embodiment 42: The dosage form of embodiment 38, wherein the mannitol is present in an amount of about 10% to about 70% by weight of the dosage form.

[0285] Embodiment 43: The dosage form of embodiment 39, wherein the microcrystalline cellulose is present in an amount of about 5% to about 50% by weight of the dosage form.

[0286] Embodiment 44: A dosage form according to embodiment 40, wherein (i) mannitol is present in an amount of about 0% to about 70% by weight of the dosage form, (ii) microcrystalline cellulose is present in an amount of about 0% to about 50% by weight of the dosage form, and (iii) the total amount of mannitol and microcrystalline cellulose is about 10% to about 70% by weight of the dosage form.

[0287] Embodiment 45: A dosage form of any of embodiments 26 to 44, wherein the weight ratio of acalabrutinib maleate (free base equivalent) to the at least one diluent is from about 1:3 to about 2:1.

[0288] Embodiment 46: A dosage form of any of embodiments 26 to 44, wherein the weight ratio of acalabrutinib maleate (free base equivalent) to the at least one diluent is from about 1:1 to about 1:2.

[0289] Embodiment 47: A dosage form according to any one of embodiments 1 to 46, wherein the at least one pharmaceutically acceptable excipient comprises at least one disintegrant.

[0290] Embodiment 48: The dosage form of embodiment 47, wherein the at least one disintegrant is present in an amount of about 0.5% to about 15% by weight of the tablet.

[0291] Embodiment 49: The dosage form of embodiment 47, wherein the at least one disintegrant is present in an amount of about 1% to about 10% by weight of the tablet.

[0292] Embodiment 50: The dosage form of embodiment 47, wherein the at least one disintegrant is present in an amount of about 2% to about 8% by weight of the tablet.

[0293] Embodiment 51: The dosage form of embodiment 47, wherein the at least one disintegrant is present in an amount of about 3% to about 7% by weight of the tablet.

[0294] Embodiment 52: The dosage form of any of embodiments 47-51, wherein the at least one disintegrant does not include an ionic disintegrant.

[0295] Embodiment 53: A dosage form according to any one of embodiments 47 to 51, wherein at least one disintegrant does not comprise sodium starch glycolate.

[0296] Embodiment 54: A dosage form according to any one of embodiments 47 to 53, wherein at least one disintegrant does not include croscarmellose sodium.

[0297] Embodiment 56: A dosage form according to any of embodiments 47-54, wherein the at least one disintegrant comprises a non-ionic disintegrant.

[0298] Embodiment 57: A dosage form according to any one of embodiments 47 to 56, wherein the at least one disintegrant comprises hydroxypropyl cellulose.

[0299] Embodiment 58: A dosage form of any of embodiments 47-56, wherein the at least one disintegrant comprises low-substituted hydroxypropyl cellulose.

[0300] Embodiment 59: A dosage form according to any one of embodiments 47 to 59, wherein the weight ratio of acalabrutinib maleate (free base equivalent) to the at least one disintegrant is from about 2:1 to about 15:1.

[0301] Embodiment 60: A dosage form according to any one of embodiments 47 to 59, wherein the weight ratio of acalabrutinib maleate (free base equivalent) to the at least one disintegrant is from about 4:1 to about 10:1.

[0302] Embodiment 61: A dosage form according to any one of embodiments 1 to 60, wherein the at least one pharmaceutically acceptable excipient comprises at least one lubricant.

[0303] Embodiment 62: The dosage form of embodiment 61, wherein the at least one lubricant is present in an amount of about 0.25% to about 4% by weight of the dosage form.

[0304] Embodiment 63: The dosage form of embodiment 61, wherein the at least one lubricant is present in an amount of about 1% to about 4% by weight of the dosage form.

[0305] Embodiment 64: A dosage form according to any of embodiments 61, wherein the at least one lubricant is present in an amount of about 1.5% to about 3.5% by weight of the dosage form.

[0306] Embodiment 65: A dosage form according to any of embodiments 61, wherein the at least one lubricant is present in an amount of about 2% to about 3% by weight of the dosage form.

[0307] Embodiment 66: A dosage form according to any one of embodiments 61 to 65, wherein the at least one lubricant does not comprise magnesium stearate.

[0308] Embodiment 67: A dosage form according to any one of embodiments 51 to 66, wherein at least one lubricant does not comprise glyceryl dibehenate.

[0309] Embodiment 68: A dosage form according to any one of embodiments 61 to 67, wherein the at least one lubricant comprises sodium stearyl fumarate.

[0310] Embodiment 69: A dosage form of any of embodiments 61 to 68, wherein the weight ratio of acalabrutinib maleate (free base equivalent) to the at least one lubricant is from about 20:1 to about 12:1.

[0311] Embodiment 70: A dosage form of any of embodiments 61 to 68, wherein the weight ratio of acalabrutinib maleate (free base equivalent) to the at least one lubricant is from about 18:1 to about 14:1.

[0312] Embodiment 71: A dosage form according to any of embodiments 1 to 70, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent, at least one disintegrant, and at least one lubricant.

[0313] Embodiment 72: The dosage form of embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 15% to about 55% (free base equivalent) by weight of the dosage form; (ii) at least one diluent in an amount of about 10% to about 70% by weight of the dosage form; (iii) at least one disintegrant in an amount of about 0.5% to about 15% by weight of the dosage form; and (iv) at least one lubricant in an amount of about 0.25% to about 4% by weight of the dosage form, wherein the sum of the individual amounts equals 100% of the total weight of the dosage form.

[0314] Embodiment 73: The dosage form of embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 20% to about 50% (free base equivalent) by weight of the dosage form; (ii) at least one diluent in an amount of about 20% to about 70% by weight of the dosage form; (iii) at least one disintegrant in an amount of about 1% to about 10% by weight of the dosage form; and (iv) at least one lubricant in an amount of about 1% to about 4% by weight of the dosage form, wherein the sum of the individual amounts equals 100% of the total weight of the dosage form.

[0315] Embodiment 74: The dosage form of embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 25% to about 50% (free base equivalent) by weight of the dosage form; (ii) at least one diluent in an amount of about 30% to about 70% by weight of the dosage form; (iii) at least one disintegrant in an amount of about 2% to about 8% by weight of the dosage form; and (iv) at least one lubricant in an amount of about 1.5% to about 3.5% by weight of the dosage form, wherein the sum of the individual amounts equals 100% of the total weight of the dosage form.

[0316] Embodiment 75: The dosage form of embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 25% to about 40% (free base equivalent) by weight of the dosage form; (ii) at least one diluent in an amount of about 40% to about 70% by weight of the dosage form; (iii) at least one disintegrant in an amount of about 3% to about 7% by weight of the dosage form; and (iv) at least one lubricant in an amount of about 2% to about 3% by weight of the dosage form, wherein the sum of the individual amounts equals 100% of the total weight of the dosage form.

[0317] Embodiment 76: The dosage form of embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 30% to about 35% (free base equivalent) by weight of the dosage form; (ii) mannitol in an amount of about 30% to about 35% by weight of the dosage form; (iii) microcrystalline cellulose in an amount of about 25% to about 30% by weight of the dosage form; (iv) hydroxypropyl cellulose in an amount of about 3% to about 7% by weight of the dosage form; and (v) sodium stearyl fumarate in an amount of about 1% to about 4% by weight of the dosage form, wherein the sum of the individual amounts equals 100% of the total weight of the dosage form.

[0318] Embodiment 77: A dosage form of any of embodiments 1 to 76, wherein the acalabrutinib maleate has a D(v,0.9) value of less than about 500 microns.

[0319] Embodiment 78: A dosage form of any of embodiments 1 to 76, wherein the acalabrutinib maleate has a D(v,0.9) value of less than about 450 microns.

[0320] Embodiment 79: A dosage form of any of embodiments 1 to 76, wherein the acalabrutinib maleate has a D(v,0.9) value of less than about 400 microns.

[0321] Embodiment 80: The dosage form of any of embodiments 1-76, wherein the acalabrutinib maleate has a D(v,0.9) value of less than about 350 microns.

[0322] Embodiment 81: A dosage form of any of embodiments 1-76, wherein the acalabrutinib maleate has a D(v,0.9) value of less than about 300 microns.

[0323] Embodiment 82: A dosage form of any of embodiments 1 to 76, wherein the acalabrutinib maleate has a D(v,0.9) value of about 20 microns to about 500 microns.

[0324] Embodiment 83: A dosage form of any of embodiments 1 to 76, wherein the acalabrutinib maleate has a D(v,0.9) value of about 50 microns to about 450 microns.

[0325] Embodiment 84: A dosage form of any of embodiments 1 to 76, wherein the acalabrutinib maleate has a D(v,0.9) value of about 75 microns to about 400 microns.

[0326] Embodiment 85: A dosage form of any of embodiments 1 to 76, wherein the acalabrutinib maleate has a D(v,0.9) value of about 75 microns to about 350 microns.

[0327] Embodiment 86: A dosage form of any of embodiments 1 to 76, wherein the acalabrutinib maleate has a D(v,0.9) value of about 100 microns to about 300 microns.

[0328] Embodiment 87: The dosage form of any of embodiments 1 to 86, wherein the dosage form is a capsule.

[0329] Embodiment 88: The capsule of embodiment 87, wherein the capsule is prepared by a process comprising roller compaction.

[0330] Embodiment 89: The dosage form of any of embodiments 1 to 86, wherein the dosage form is a tablet.

[0331] Embodiment 90: A dosage form according to any one of embodiments 1 to 86, wherein the dosage form is a film-coated tablet.

[0332] Embodiment 91: The tablet of embodiment 89 or 90, wherein the tablet is prepared by a process comprising direct compression.

[0333] Embodiment 92: The tablet of embodiment 89 or 90, wherein the tablet is prepared by a process comprising roller compaction.

[0334] Embodiment 93: A tablet according to any of embodiments 89 to 92, wherein the tablet has a tensile strength of from about 1.5 MPa to about 5.0 MPa.

[0335] Embodiment 94: A tablet according to any of embodiments 89 to 92, wherein the tablet has a tensile strength of about 2.0 MPa to about 4.0 MPa.

[0336] Embodiment 95: A tablet according to any of embodiments 89 to 94, wherein the tensile strength of the tablet does not decrease by more than 10% from its initial tensile strength after the tablet is stored in a blister pack at 40°C and 75% relative humidity for 6 months.

[0337] Embodiment 96: A tablet according to any of embodiments 89 to 94, wherein the tensile strength of the tablet does not decrease by more than 8% from its initial tensile strength after the tablet is stored in a blister pack at 40°C and 75% relative humidity for 6 months.

[0338] Embodiment 97: A tablet according to any of embodiments 89 to 94, wherein the tensile strength of the tablet does not decrease by more than 5% from its initial tensile strength after the tablet is stored in a blister pack at 40°C and 75% relative humidity for 6 months.

[0339] Embodiment 98: A method of treating a condition in a subject suffering from or susceptible to a BTK-mediated condition, comprising administering to the subject once daily or twice daily a solid pharmaceutical dosage form of any of embodiments 1-97.

[0340] The specification set forth herein uses examples to disclose the invention and to enable any person skilled in the art to practice the invention (e.g., make and use any of the disclosed salts, materials, or compositions, and perform any of the disclosed methods or processes). The patentable scope of the invention is defined by the claims, and may include other examples that those skilled in the art recognize. Such other examples are intended to be within the scope of the claims if they have elements that do not differ from the literal language of the claims, or if they contain equivalent elements that have insubstantial differences from the literal language of the claims. While preferred embodiments of the invention have been shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the invention. The section headings used in this section and throughout the disclosure are not intended to be limiting.

[0341] All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of these references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or any portion of any reference) is relevant prior art (or any prior art). Applicant reserves the right to challenge the accuracy and pertinence of the cited references. The present invention includes the following aspects: [Item 1] A solid pharmaceutical dosage form for oral administration to humans, comprising about 75 mg to about 125 mg (free base equivalent) of acalabrutinib maleate and at least one pharmaceutically acceptable excipient, wherein the dosage form is conditions wherein at least about 75% of the acalabrutinib maleate dissolves within about 30 minutes as measured in an in vitro dissolution test conducted using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and A solid pharmaceutical dosage form wherein at least about 75% of the acalabrutinib maleate dissolves within about 60 minutes as measured in an in vitro dissolution test conducted using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM. [Item 2] The dosage form is conditions wherein at least about 80% of the acalabrutinib maleate dissolves within about 15 minutes as measured in an in vitro dissolution test conducted using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and Item 1. The dosage form of item 1, wherein at least about 80% of the acalabrutinib maleate dissolves within about 20 minutes as measured in an in vitro dissolution test performed using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM. [Item 3] The dosage form of Item 1 or 2, wherein the acalabrutinib maleate is crystalline acalabrutinib maleate monohydrate Form A. [Item 4] The dosage form according to any one of Items 1 to 3, wherein the at least one pharmaceutically acceptable excipient is selected from at least one diluent, at least one disintegrant, and at least one lubricant. [Item 5] The dosage form of any one of Items 1 to 4, wherein the dissolution rate of the acalabrutinib maleate in the 5 mM phosphate pH 6.8 dissolution medium does not decrease by more than 20% from its initial dissolution rate after storage of the dosage form in suitable packaging at 40°C and 75% relative humidity for 6 months. [Item 6] The dosage form of any one of Items 1 to 5, wherein no more than about 5% (w / w) of the acalabrutinib maleate present in the dosage form degrades after storage of the dosage form in suitable packaging at 40°C and 75% relative humidity for 6 months. [Item 7] The dosage form is bioequivalent to a 100 mg Calquence® capsule when orally administered to a fasting human subject not receiving a gastric acid reducing agent, wherein the relative mean C max , AUC (0-t) , and AUC (0-∞) Item 7. The dosage form according to any one of Items 1 to 6, which is bioequivalent when the confidence interval of the above is within the range of 80% to 125%. [Item 8] The dosage form of any one of Items 1 to 7, wherein the acalabrutinib maleate is present in an amount of about 100 mg (free base equivalent). [Item 9] The dosage form according to any one of Items 1 to 8, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent. [Item 10] The dosage form described in Item 9, wherein the at least one diluent does not affect the stability of the primary amine moiety of acalabrutinib. [Item 11] The dosage form according to Item 9 or 10, wherein the at least one diluent comprises a plastic diluent and a brittle diluent. [Item 12] The dosage form of any one of Items 9 to 11, wherein the weight ratio of acalabrutinib maleate (free base equivalent) to the at least one diluent is about 1:3 to about 2:1. [Item 13] The dosage form according to any one of Items 1 to 12, wherein the at least one pharmaceutically acceptable excipient comprises at least one disintegrant. [Item 14] The dosage form according to Item 13, wherein the at least one disintegrant does not include an ionic disintegrant. [Item 15] The dosage form of Item 13 or 14, wherein the weight ratio of acalabrutinib maleate (free base equivalent) to the at least one disintegrant is about 2:1 to about 15:1. [Item 16] The dosage form is acalabrutinib maleate in an amount of about 15% to about 55% (free base equivalent) by weight of the dosage form; at least one diluent in an amount of about 10% to about 70% by weight of the dosage form; at least one disintegrant in an amount of about 0.5% to about 15% by weight of the dosage form; and at least one lubricant in an amount of about 0.25% to about 4% by weight of the dosage form; Item 5. The dosage form according to item 4, wherein the sum of the individual amounts is equal to 100% of the total weight of the dosage form. [Item 17] The dosage form is acalabrutinib maleate in an amount of about 30% to about 35% (free base equivalent) by weight of the dosage form; and mannitol in an amount of about 30% to about 35% by weight of the dosage form; microcrystalline cellulose in an amount of about 25% to about 30% by weight of the dosage form; Hydroxypropyl cellulose in an amount of about 3% to about 7% by weight of the dosage form; and sodium stearyl fumarate in an amount of about 1% to about 4% by weight of the dosage form; Item 5. The dosage form according to item 4, wherein the sum of the individual amounts is equal to 100% of the total weight of the dosage form. [Item 18] The acalabrutinib maleate has a D of about 20 microns to about 500 microns. (v,0.9) Item 18. The dosage form according to any one of items 1 to 17, having a value. [Item 19] The dosage form according to any one of Items 1 to 18, wherein the dosage form is a tablet. [Item 20] The tablet according to Item 19, wherein the tablet has a tensile strength of about 1.5 MPa to about 5.0 MPa. [Item 21] The tablet according to Item 20, wherein the tensile strength of the tablet does not decrease by more than 10% from its initial tensile strength after storing the tablet in a blister pack at 40°C and 75% relative humidity for 6 months. [Item 22] A method for treating a BTK-mediated condition in a subject suffering from or susceptible to the condition, comprising administering to the subject the solid pharmaceutical dosage form of any one of Items 1 to 21 once daily or twice daily.

Claims

1. A solid pharmaceutical tablet comprising 100 mg (free base equivalent) of acalabrutinib maleate for oral administration to humans, The tablet further comprises Mannitol and microcrystalline cellulose in a total amount of 10% to 70% by weight of the tablet; low-substituted hydroxypropyl cellulose in an amount of 0.5% to 15% by weight of the tablet; and sodium stearyl fumarate in an amount of 0.25% to 4% by weight of the tablet; the sum of the amount of acalabrutinib maleate, the amount of mannitol, the amount of microcrystalline cellulose, the amount of low-substituted hydroxypropyl cellulose, and the amount of sodium stearyl fumarate is equal to 100% of the total weight of the tablet; The tablet wherein at least 75% of the acalabrutinib maleate dissolves within 30 minutes as measured in an in vitro dissolution test conducted at 37±0.5°C using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and A solid pharmaceutical tablet wherein at least 75% of the acalabrutinib maleate dissolves within 60 minutes as measured in an in vitro dissolution test conducted at 37±0.5°C using a USP Paddle Apparatus 2, a 900 mL dissolution volume, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM.

2. The tablet wherein at least 80% of the acalabrutinib maleate dissolves within 15 minutes as measured in an in vitro dissolution test conducted at 37±0.5°C using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 0.1 N hydrochloric acid dissolution medium, and a paddle rotation speed of 50 RPM; and 2. The tablet of claim 1, wherein at least 80% of the acalabrutinib maleate dissolves within 20 minutes as measured in an in vitro dissolution test conducted at 37±0.5°C using a USP Paddle Apparatus 2, a dissolution volume of 900 mL, a 5 mM phosphate pH 6.8 dissolution medium, and a paddle rotation speed of 75 RPM.

3. 2. The tablet of claim 1, wherein the acalabrutinib maleate is acalabrutinib maleate monohydrate.

4. 2. The tablet of claim 1, wherein the acalabrutinib maleate is crystalline acalabrutinib maleate monohydrate form A having an X-ray powder diffraction pattern consisting of peaks at 5.3, 9.8, 10.6, 11.6, and 19.3°2θ±0.2°2θ.

5. 5. The tablet of any one of claims 1 to 4, wherein the dissolution rate of the acalabrutinib maleate in the 5 mM phosphate pH 6.8 dissolution medium does not decrease by more than 20% from its initial dissolution rate after storage of the tablet in a blister pack at 40°C and 75% relative humidity for 6 months.

6. 6. A tablet according to any one of claims 1 to 5, wherein no more than 5% (w / w) of the acalabrutinib maleate present in the tablet is degraded after the tablet is stored in a blister pack at 40°C and 75% relative humidity for 6 months.

7. The tablet is bioequivalent to a capsule containing 100 mg of acalabrutinib free base when orally administered to fasted human subjects not receiving a gastric acid reducing agent, wherein the relative mean C ｍａｘ , AUC （０－ｔ） , and AUC （０－∞） is bioequivalent if the confidence interval of and having a total capsule fill weight in size 1 blue / yellow gelatin capsules of 240 mg.

8. The tablet, the mannitol and microcrystalline cellulose in a total amount of 20% to 70% by weight of the tablet; the low-substituted hydroxypropyl cellulose in an amount of 1% to 10% by weight of the tablet; and the sodium stearyl fumarate in an amount of 1% to 4% by weight of the tablet; 5. The tablet of any one of claims 1 to 4, wherein the sum of the amount of acalabrutinib maleate, the amount of mannitol, the amount of microcrystalline cellulose, the amount of low-substituted hydroxypropyl cellulose, and the amount of sodium stearyl fumarate is equal to 100% of the total weight of the tablet.

9. The tablet, the mannitol and microcrystalline cellulose in a total amount of 30% to 70% by weight of the tablet; the low-substituted hydroxypropyl cellulose in an amount of 2% to 8% by weight of the tablet; and the sodium stearyl fumarate in an amount of 1.5% to 3.5% by weight of the tablet; 5. The tablet of any one of claims 1 to 4, wherein the sum of the amount of acalabrutinib maleate, the amount of mannitol, the amount of microcrystalline cellulose, the amount of low-substituted hydroxypropyl cellulose, and the amount of sodium stearyl fumarate is equal to 100% of the total weight of the tablet.

10. The tablet, the mannitol and microcrystalline cellulose in a total amount of 40% to 70% by weight of the tablet; the low-substituted hydroxypropyl cellulose in an amount of 3% to 7% by weight of the tablet; and the sodium stearyl fumarate in an amount of 2% to 3% by weight of the tablet; 5. The tablet of any one of claims 1 to 4, wherein the sum of the amount of acalabrutinib maleate, the amount of mannitol, the amount of microcrystalline cellulose, the amount of low-substituted hydroxypropyl cellulose, and the amount of sodium stearyl fumarate is equal to 100% of the total weight of the tablet.

11. The tablet the mannitol in an amount of 30% to 35% by weight of the tablet; the microcrystalline cellulose in an amount of 25% to 30% by weight of the tablet; the low-substituted hydroxypropyl cellulose in an amount of 3% to 7% by weight of the tablet; and the sodium stearyl fumarate in an amount of 1% to 4% by weight of the tablet; 5. The tablet of any one of claims 1 to 4, wherein the sum of the amount of acalabrutinib maleate, the amount of mannitol, the amount of microcrystalline cellulose, the amount of low-substituted hydroxypropyl cellulose, and the amount of sodium stearyl fumarate is equal to 100% of the total weight of the tablet.

12. The acalabrutinib maleate has a D （ｖ，０．９） The tablet according to any one of claims 1 to 4, having a value.

13. The tablet of any one of claims 1 to 4, wherein the tablet further comprises a coating.

14. The tablet according to any one of claims 1 to 4, wherein the tablet has a tensile strength of 1.5 MPa to 5.0 MPa.

15. 5. The tablet of any one of claims 1 to 4, wherein the tensile strength of the tablet does not decrease by more than 10% from its initial tensile strength after storing the tablet in a blister pack at 40°C and 75% relative humidity for 6 months.

16. The tablet of any one of claims 1 to 4 for treating B-cell hematological malignancies.

17. 17. The tablet of claim 16, wherein the B-cell hematological malignancy is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic leukemia.

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