HK40083774A - Acalabrutinib maleate dosage forms - Google Patents
Acalabrutinib maleate dosage forms Download PDFInfo
- Publication number
- HK40083774A HK40083774A HK62023073027.2A HK62023073027A HK40083774A HK 40083774 A HK40083774 A HK 40083774A HK 62023073027 A HK62023073027 A HK 62023073027A HK 40083774 A HK40083774 A HK 40083774A
- Authority
- HK
- Hong Kong
- Prior art keywords
- dosage form
- maleate
- acaracinib
- dissolution
- weight
- Prior art date
Links
Description
Technical Field
The present disclosure generally relates to: (a) A solid pharmaceutical dosage form comprising acarabtinib maleate; (b) Methods of treating B cell malignancies and/or other disorders using such pharmaceutical dosage forms; (c) A kit comprising such a pharmaceutical dosage form and optionally a second pharmaceutical dosage form containing another therapeutic agent; (d) processes for preparing such pharmaceutical dosage forms; and (e) pharmaceutical dosage forms prepared by such methods.
Background
Acarabtinib is a selective covalent Bruton Tyrosine Kinase ("BTK") inhibitor. It is a medicineThe active pharmaceutical ingredient(s) in (a), has been 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. />Sold as a capsule dosage form containing 100mg of crystalline acaracinib free base (especially the form a anhydrate). International publication WO 2017/002095 reports anhydrous form A of acaracinib, in additionCrystalline acaracinib free base forms and crystalline acaracinib salt forms of (a), including, for example, citrate, fumarate, gentisate, maleate, oxalate, phosphate, sulfate, and L-tartrate salts. />The prescription information of (a) suggests avoiding co-administration with gastric acid-reducing agents, since such agents may reduce the plasma concentration of acaracinib. Therefore, there is a need for pharmaceutical formulations of acaracinib that reduce the potential effect of antacids on acaracinib plasma concentrations when co-administered with an acaracinib formulation.
Disclosure of Invention
In one aspect, the present disclosure relates to a solid pharmaceutical dosage form for oral administration to a human comprising about 75mg to about 125mg (free base equivalent) acarabtinib maleate and at least one pharmaceutically acceptable excipient, wherein the dosage form satisfies the following conditions:
at least about 75% of the acaracitinib maleate dissolves in about 30 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium, and 50RPM paddle rotation; and
at least about 75% of the acaracitinib maleate dissolves in about 60 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate ph6.8 dissolution medium, and paddle rotation speed of 75 RPM.
In a further aspect, the solid pharmaceutical dosage form comprises from about 75mg to about 100mg (free base equivalent) of acaracinib maleate. In a still further aspect, the acaracinib maleate is present as acaracinib maleate monohydrate, e.g., crystalline acaracinib maleate monohydrate form a.
In another aspect, the present disclosure relates to the solid pharmaceutical dosage form described above, wherein the dissolution rate of acarabtinib maleate in a 5mM phosphate pH6.8 dissolution medium does not decrease by more than 20% from its initial dissolution rate after six months storage at 40 ℃ and 75% relative humidity in suitable packaging.
In another aspect, the present disclosure relates to one or more of the above solid pharmaceutical dosage forms, wherein no more than about 5% (w/w) of the acaracinib maleate present in the dosage form degrades after six months of storage in suitable packaging at 40 ℃ and 75% relative humidity.
In another aspect, the present disclosure relates to one or more of the above solid pharmaceutical dosage forms, wherein the dosage form is bioequivalent to 100mg when orally administered to a fasting human subject that is not administered a gastric antacidCapsules wherein the relative average C of the dosage forms max 、AUC (0-t) And AUC (0-∞) Is compared with a confidence interval of 100mg>The dosage form is bioequivalent when the capsule is within 80% to 125%.
In another aspect, the present disclosure relates to one or more of the above solid pharmaceutical dosage forms, wherein the dosage form, when administered twice daily to a population of fasting human subjects, satisfies one or more of the following pharmacokinetic conditions for acarabtinib:
average C in a population of human subjects max Values from about 400ng/mL to about 900ng/mL;
mean AUC in 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 in a population of human subjects (0-∞) Values are about 350 ng-hr/mL to about 1900 ng-hr/mL.
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 of at least about 90% in peripheral blood mononuclear cells when administered twice daily to a human subject.
In another aspect, the present disclosure relates to one or more of the above solid pharmaceutical dosage forms, wherein the dosage form comprises:
acaracitinib maleate in an amount from about 15% to about 55% by weight of the dosage form;
at least one diluent in an amount from about 10% to about 70% by weight of the dosage form;
at least one disintegrant in an amount from about 0.5% to about 15% by weight of the dosage form; and
at least one lubricant in an amount from about 0.25% to about 4% by weight of the dosage form; and is
Wherein the sum of the amounts equals 100% of the total weight of the dosage form.
In another aspect, the present disclosure relates to one or more of the above solid pharmaceutical dosage forms, wherein the dosage form comprises:
acaracitinib maleate monohydrate in an amount from about 30% to about 35% (free base equivalents) 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 from 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 from about 1% to about 4% by weight of the dosage form; and is
Wherein the sum of the amounts equals 100% of the total weight of the dosage form.
Drawings
Figure 1 is a representative XRPD diffractogram of crystalline acaracinib maleate monohydrate form a.
Figure 2 shows the dissolution profile of the phosphate, oxalate and maleate salts of acaracitinib in simulated gastric fluid/FaSSIF-V2 medium.
Figure 3 shows the dissolution spectra of the phosphate, oxalate and maleate salts of acarabtinib in deionized water/FaSSIF-V2 medium.
Figure 4 is a drawing of the dynamic vapour sorption of acaracinib phosphate.
Figure 5 is a thermogravimetric analysis of acaracinib phosphate.
Figure 6 is an XRPD diffractogram of acaracinib phosphate.
FIG. 7 is a thermogravimetric analysis of acaracinib oxalate.
Figure 8 is a drawing of the dynamic vapour sorption of acaracinib oxalate.
Figure 9A is a thermogravimetric analysis of acaracinib maleate.
Figure 9B is a thermogravimetric analysis of acarabtinib maleate performed under an alternative set of conditions.
Figure 10A is a graph of dynamic vapor sorption of a first sample of acaracinib maleate.
Figure 10B is a drawing of the dynamic vapor sorption of a second higher quality sample of acarabtinib maleate.
Figure 11 shows the dissolution profile of micronized and unmilled acarabtinib maleate in simulated gastric fluid/FaSSIF-V2 medium.
FIG. 12 shows the dissolution profile of micronized and unmilled acarabtinib maleate in deionized water/FaSSIF-V2 medium.
Figure 13 shows the solubility of acaracinib maleate and acaracinib free base in various buffer solutions compared to the final pH.
Fig. 14 shows the dissolution profiles obtained from the low pH test of the acartinib maleate tablets T16, T17 and T18 and the acartinib free base capsule C1 under sink conditions.
Fig. 15 shows the dissolution profiles obtained from the neutral pH low ionic strength test of acaracinib maleate tablets T16, T17 and T18 under sink conditions.
Figure 16 shows the dissolution profiles obtained from the neutral pH high ionic strength test of acaracinib maleate tablet T13 and acaracinib free base capsule C2.
Fig. 17 shows the dissolution profiles of the acamprintine maleate tablet T1 and the acamprintine free base capsule C1 obtained from neutral medium without buffer capacity (i.e. stomach under conditions similar to proton pump inhibitor treatment).
Fig. 18 shows the dissolution profile of acaracinib maleate tablets T13 and acaracinib free base capsules C1 obtained from neutral medium without buffer capacity.
Fig. 19 shows the dissolution profile of acaracinib maleate tablet T19 under varying pH conditions.
Figure 20 shows the dissolution profile of acaracinib maleate tablet T19 and acaracinib free base capsule C3 under varying pH conditions.
Figure 21 is a graph of the cumulative available fraction (%) of acartinib for acartinib maleate tablet T19 and acartinib free base capsule C2 versus time (minutes) when evaluated in the TIM-1 system under gastric conditions associated with an acidic gastric compartment and also under gastric conditions associated with administration of a proton pump inhibitor or an acid reducing agent in combination.
FIG. 22 shows acaracinib maleate tablet T10 (D) (v,0.9) ≈150μm)、T11(D (v,0.9) ≈16μm)、T13(D (v,0.9) 500 μm) and T15 (D) (v,0.9) About 70 μm).
Figure 23 shows the dissolution profile of acarabtinib maleate tablets T10, T11, T13 and T15 (drug loading of 26 wt%) in 5mM sodium phosphate buffer medium.
Figure 24 shows the dissolution profile of acarabinib maleate tablets T9, T2 and T14 (43 wt% drug loading) in 5mM sodium phosphate buffer medium.
Figure 25 reports the results of in vivo studies performed in dog models to measure AUC for acartinib free base and acartinib maleate when co-administered with omeprazole (0-24) The value is obtained.
Figure 26 shows the dissolution profile of several binary mixtures of disintegrant and acaracinib maleate (1:5 ratio) in deionized water medium.
Figure 27 shows the dissolution profiles in deionized water medium of several binary mixtures of lubricant and acarabtinib maleate (1 ratio 15).
Fig. 28 shows the dissolution profile of the tablet cores T2 and T3 in a deionized water medium.
Fig. 29 shows the dissolution profile of the tablet cores T6 and T8 in a deionized water medium.
Fig. 30 shows the dissolution profile of the tablet cores T4 and T5 in a deionized water medium.
Fig. 31 provides a schematic of a process for preparing the acaracinib maleate tablet T21 of example 4.
Detailed Description
I. Definition of
Unless defined otherwise, 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.
When ranges are used to describe, for example, amounts, all combinations and subcombinations of ranges and specific embodiments are intended to be included.
The singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise.
The use of the term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. This variation is generally from 0% to 15%, preferably from 0% to 10%, more preferably from 0% to 5% of the number or range of values. In many cases, the term "about" may include numbers that are rounded to the nearest significant figure.
The term "acaracitinib" refers to the international non-proprietary name (INN) of the compound 4- { 8-amino-3- [ (2S) -1- (but-2-alkynoyl) pyrrolidin-2-yl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (pyridin-2-yl) benzamide, which has the chemical structure:
international publication WO 2013/010868 discloses acaracinib (example 6) and describes the synthesis of acaracinib. International publication WO 2020/043787 further describes the synthesis of acaracinib. International publication WO 2013/010868 and International publication WO 2020/043787 are each incorporated by reference in their entirety.
The term "acaracitinib maleate monohydrate" refers to crystalline acaracib maleate monohydrate, including crystalline form a of acaracib maleate monohydrate. Example 6.2 of international publication No. WO 2017/002095 describes the preparation of crystalline form a of acaracinib maleate monohydrate. International publication No. WO 2017/002095 is incorporated by reference in its entirety. Acaracitinib maleate monohydrate form a may also be referred to by alternative nomenclature acaracib maleate monohydrate form 1. Unless otherwise indicated, any reference in this disclosure to the amount of acamprovinib, acamprovinib maleate or acamprovinib maleate monohydrate is based on acamprovinib free base equivalents. For example, 100mg refers to 100mg of acamprovinib free base or an equivalent amount of acamprovinib maleate or acamprovinib maleate monohydrate.
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, which has the chemical structure:
ACP-5862 is an active metabolite of acaracinib.
The term "AUC (0-24) "refers to the area under the plasma concentration-time curve from time 0 (time of administration) to 24 hours post-administration, as calculated by the linear trapezoidal method.
The term "AUC (0-∞) "refers to the area under the plasma concentration-time curve from time 0 (time of administration) to infinity (∞), as calculated by the linear trapezoidal method.
The term "BID" refers to twice daily (bis in die), twice daily (twin a day), or twice daily (twin day).
The term "C max "refers to the maximum plasma concentration observed throughout the sampling period.
The terms "co-administration," "combination with … …," and "combination" may refer to the administration of two or more therapeutic agents. In one aspect, "combining" can refer to administering simultaneously (e.g., the two agents are administered in separate dosage forms, but substantially simultaneously). In another aspect of the invention, "combination" may refer to sequential administration (e.g., wherein a first agent is administered followed by a delay, followed by administration of a second or additional agent). In the case of sequential application, the components of the delay application side-by-side should neither be too long nor too short so as not to lose the combined benefits.
Unless the context requires otherwise, the terms "comprises," "comprising," and "comprising" are used in an explicit sense to mean that they are interpreted inclusively rather than exclusively, and that the applicant intends to interpret each of those terms in interpreting the patent (including the claims below).
The term "crystalline" as applied to acamprovinib, acamprovinib maleate or acamprovinib monohydrate refers to a solid state form in which the molecules are arranged to form a distinguishable lattice that (i) comprises distinguishable unit cells, and (ii) produces a diffraction peak when subjected to X-ray radiation.
The term "crystalline purity" refers to the crystalline purity of acamprovinib, acamprovinib maleate or acamprovinib maleate monohydrate for a particular crystalline form as determined by X-ray powder diffraction analysis methods.
The term "crystallization" as used throughout this application may refer to crystallization and/or recrystallization, depending on the applicable circumstances associated with the preparation of acaracinib, acaracinib maleate or acaracinib maleate monohydrate.
The term "D" as used in this application (0.1) "and" D (v,0.1) "means that 10% of the total volume of material in the sample has a particle size diameter below a specified value as determined by laser diffraction.
The term "D" as used in this application (0.5) "and" D (v,0.5) "indicating the total volume of material in the sample50% have a particle size diameter below a specified value as determined by laser diffraction.
The term "D" as used in this application (0.9) "and" D (v,0.9) By "is meant that 90% of the total volume of material in the sample has a particle size diameter below a specified value as determined by laser diffraction.
The term "pharmaceutically acceptable" (e.g., in the context of a "pharmaceutically acceptable diluent" or "pharmaceutically acceptable disintegrant") refers to a material that is compatible with administration to a subject, e.g., the material does not cause an undesirable biological effect. Examples of pharmaceutically acceptable Excipients are described in "Handbook of Pharmaceutical Excipients [ Handbook of Pharmaceutical Excipients ]", edited by Rowe et al (Pharmaceutical Press [ Pharmaceutical Press ], 7 th edition, 2012).
"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 inert ingredients. Except that any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with alcazatinib, alcazatinib maleate or acarabinib maleate monohydrate, its use in the therapeutic compositions of the invention is contemplated.
The term "Q" refers to the amount of active substance (Q) in a sample that dissolves over a specified time, expressed as a percentage of the total amount of active substance in the sample.
The term "QD" refers to once daily (quaque die), once daily (once a day), or once daily (once a day).
The term "T max "refers to the maximum plasma concentration (C) observed max ) Time of (d).
The terms "treating" and "treatment" refer to ameliorating, inhibiting, eradicating, reducing the severity of, reducing the frequency of occurrence of, reducing the risk of, or delaying the onset of a disorder.
The abbreviations listed in table 1 below have the meanings indicated in the table.
TABLE 1
II.Solid dosage form
The present disclosure relates in part to solid pharmaceutical dosage forms comprising acaracinib maleate, in particular crystalline acaracinib maleate monohydrate. According to the biopharmaceutical classification system ("BCS"), acarabtinib is a BCS class II drug substance, which means that it has good permeability but low solubility in the gastrointestinal tract. See Pepin, X.J.H., et al, "Bridging in vitro dissolution and in vivo expression for acalabutinib [ in vitro solubilization and in vivo exposure of bridged acarabtinib]A mechanical PBPK model for IR formulation compliance, proton pump inhibitor drug interactions, and administration with acidic joints [ mechanical PBPK model for IR formulation comparison, proton pump inhibitor drug interactions, and acid juice administration]"European Journal of pharmaceuticals and biopharmaceuticals [ European Journal of biopharmaceuticals]142:435-448 (2019). Bioavailability of BCS class II drug substances, including acarabtinib, is generally limited by their dissolution rate and/or solvation. Furthermore, the acaracinib free base exhibits a pH dependent solubility, which decreases as the pH increases to the maximum basic pKa (i.e., about pH6, where the acaracinib is mostly unionized). Increase in administrationThe gastric pH of the subject (e.g., in a subject concurrently taking a proton pump inhibitor or other gastric antacid) can reduce the solubility of acartinib in the stomach and potentially lead to reduced bioavailability and/or greater intra-and inter-subject variability in acartinib pharmacokinetics. The disclosure relates toIn addition, it was found that solid pharmaceutical dosage forms containing acarabtinib maleate, as described below, have acceptable physical and pharmacological properties (e.g., solubility, stability, manufacturability, pharmacokinetics, etc.) and, although under normal acidic stomach conditions, are comparable to currently marketed £ er @>The capsule dosage form is essentially bioequivalent, but the pharmacokinetic variability of acaracinib is less under the broader gastric pH conditions. These solid dosage forms provide an additional therapeutic option for the treatment of conditions including B cell malignancies (e.g., chronic lymphocytic leukemia, small lymphocytic leukemia, and mantle cell lymphoma).
In some embodiments, the present disclosure relates, in part, to a solid pharmaceutical dosage form for oral administration to a human comprising from about 75mg to about 125mg (free base equivalent) acarabtinib maleate and at least one pharmaceutically acceptable excipient, wherein the dosage form satisfies the following condition:
at least about 75% of the acaracitinib maleate dissolves in about 30 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium, and 50RPM paddle rotation; and
at least about 75% of the acaracitinib maleate dissolves in about 60 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate ph6.8 dissolution medium, and paddle rotation speed of 75 RPM.
The 0.1N hydrochloric acid dissolution medium is considered to be representative of a fasted stomach, while the 5mM phosphate ph6.8 dissolution is considered to be representative of the worst case of a stomach treated with a gastric acid-reducing agent. In one aspect, the dosage form satisfies the following conditions:
at least about 75% of the acaracitinib maleate dissolves in about 20 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium, and 50RPM paddle rotation; and
at least about 75% of the acarabtinib maleate dissolved in about 45 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate ph6.8 dissolution medium and paddle rotation speed of 75 RPM.
In another aspect, the dosage form satisfies the following conditions:
at least about 80% of the acarabtinib maleate dissolves in about 20 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium and 50RPM paddle rotation; and
at least about 80% of the acarabtinib maleate dissolved in about 30 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate ph6.8 dissolution medium and paddle rotation speed of 75 RPM.
In another aspect, the dosage form satisfies the following conditions:
at least about 80% of the acaracitinib maleate dissolves in about 15 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium, and 50RPM paddle rotation; and
at least about 80% of the acaracitinib maleate dissolves in about 20 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate ph6.8 dissolution medium, and paddle rotation speed of 75 RPM.
In some embodiments, a solid pharmaceutical dosage form of the present disclosure comprises from about 75mg to about 125mg of acaracinib maleate (free base equivalent). In one aspect, the dosage form comprises from about 75mg to about 100mg acarabtinib maleate (free base equivalent). In another aspect, the dosage form comprises from about 75mg to about 80mg of acaracinib maleate (free base equivalent). In another aspect, the dosage form comprises from about 80mg to about 85mg of acaracinib maleate (free base equivalent). In another aspect, the dosage form comprises from about 85mg to about 90mg of acaracinib maleate (free base equivalent). In another aspect, the dosage form comprises from about 90mg to about 95mg of acamprovinib maleate (free base equivalent). In another aspect, the dosage form comprises from about 95mg to about 100mg of acamprovinib maleate (free base equivalent). In another aspect, the dosage form comprises about 75mg acaracinib maleate (free base equivalent). In another aspect, the dosage form comprises about 80mg of acamprovinib maleate (free base equivalent). In another aspect, the dosage form comprises about 85mg acaracinib maleate (free base equivalent). In another aspect, the dosage form comprises about 90mg acaracinib maleate (free base equivalent). In another aspect, the dosage form comprises about 95mg acarabtinib maleate (free base equivalent). In another aspect, the dosage form comprises about 100mg acaracinib maleate (free base equivalent).
In some embodiments, the acaracinib maleate is acaracinib maleate monohydrate. In one aspect, the acaracitinib maleate monohydrate is crystalline acaracinib maleate monohydrate. In another aspect, the crystalline acaracinib maleate is crystalline acaracinib maleic acid monohydrate form a having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: an X-ray powder diffraction pattern wherein at least five peaks are selected from the group consisting 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, 24.8, 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, with peak positions measured in ° 2 θ ± 0.2 ° 2 θ. In another aspect, crystalline acaracinib maleate monohydrate form a has an X-ray powder diffraction pattern comprising peaks at 5.3, 9.8, 10.6, 11.6, and 19.3 ° 2 Θ ± 0.2 ° 2 Θ. In another aspect, the X-ray powder diffraction pattern is substantially in accordance with the X-ray powder diffraction pattern of FIG. 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 reflectance mode. In another aspect, the crystalline acaracinib maleate monohydrate of any of the preceding embodiments has a stoichiometry relative to acaracinib about equal to the monohydrate. International publication No. WO 2017/002095 describes suitable X-ray powder diffraction measurement conditions.
In some embodiments, the dosage form comprises acaracinib maleate, wherein the acaracinib maleate has a crystalline purity of at least about 80% by weight of the acaracinib 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 acaracinib maleate is acaracinib maleate monohydrate. In another aspect, the acaracinib maleate is acaracinib maleate monohydrate form a.
In some embodiments, the dosage form comprises acamprovinib maleate, wherein the acamprovinib maleate has a crystalline purity of at least about 95% by weight of the acamprovinib present in the dosage form. In one aspect, the acaracinib maleate is acaracinib maleate monohydrate. In another aspect, the acaracinib maleate is acaracinib 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 other aspects, the crystalline purity of acaracinib maleate is at least about 95% by weight of the acaracinib present in the dosage form and comprises less than about 2% by weight of the impurity (2Z) -4- [ (2S) -2- { 8-amino-1- [4- (2-pyridylcarbamoyl) phenyl ] imidazo [1,5-a ] pyrazin-3-yl } -1-pyrrolidinyl ] -4-oxo-2-butenoic acid having the chemical structure shown below:
in another aspect, the acaracitinib maleate comprises less than about 1.5% by weight impurities. In another aspect, the acaracitinib maleate comprises less than about 1% by weight of impurities. In another aspect, the acaracitinib maleate comprises less than about 0.5% by weight of impurities. In another aspect, the acaracitinib maleate is substantially free of impurities.
The choice of the salt of the compound, rather than the free form of the compound, does not necessarily improve the solubility and absorption of the compound in the gastrointestinal tract to the desired degree. In addition, salts of compounds can differ significantly in physical and other properties that affect whether the salt is suitable for use in a pharmaceutical dosage form. For example, in the acidic environment of the stomach and in the pH6 to pH 7.5 environment of the intestine, rapid conversion of the salt to the relatively insoluble free form can result in precipitation of a portion of the free form. This precipitation of the free form results in a smaller amount of the administered dose being absorbed by the gastrointestinal tract, which results in a lower overall bioavailability of the compound. Surface characteristics (e.g., affecting wettability) and particle size (e.g., affecting dissolution rate) are also among the factors that affect the selected salt properties of the dosage form.
For example, the citrate, fumarate, gentisate, napadisylate, nitrate, oxalate, phosphate, sulfate, and L-tartrate salts of acartinib are all determined to be unsuitable for use in the solid pharmaceutical dosage forms of the present disclosure. According to pK a Evidence of values and/or complex solid state behavior, excluding citrate, fumarate, gentisate and L-tartrate from consideration. For example, naphthalene disulfonate has crystallinity problems. Nitrates are not suitable for large scale production and are generally not conducive to use in pharmaceutical products. Oxalates, phosphates and sulfates exhibit complex hydrate behavior and are considered unsuitable for commercial production.
In fact, the acaracinib maleate samples initially tested were considered unlikely to reach the solubility and dissolution rate required to overcome the limitations of acaracinib free base in patients with elevated gastric pH. Furthermore, although crystalline acaracinib maleate monohydrate form a is thermodynamically stable under ambient conditions, it also exhibits solid state properties that were originally thought to present challenges to the commercial supply manufacturing of pharmaceutical products.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form wherein the dissolution rate of acarabtinib maleate does not decrease by more than 20% from its initial dissolution rate after six months storage in suitable packaging at 40 ℃ and 75% relative humidity in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate pH6.8 dissolution medium, and 75RPM paddle rotation. In one aspect, the dissolution rate does not decrease by more than 10% from its initial dissolution rate after six months of storage of the dosage form in suitable packaging at 40 ℃ and 75% relative humidity. In one aspect, the dissolution rate does not decrease by more than 15% from its initial dissolution rate after six months of storage of the dosage form in suitable packaging at 40 ℃ and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 5% from its initial dissolution rate after six months of storage of the dosage form in suitable packaging at 40 ℃ and 75% relative humidity. In another aspect, the dissolution rate does not decrease more than 3% from its initial dissolution rate after six months of storage of the dosage form in suitable packaging at 40 ℃ and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 2% from its initial dissolution rate after six months of storage of the dosage form in suitable packaging at 40 ℃ and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 1% from its initial dissolution rate after six months of storage of the dosage form in suitable packaging at 40 ℃ and 75% relative humidity. In one aspect, the package is a blister package, such as an aluminum blister. In another aspect, the package is a sealed HDPE bottle with desiccant.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form wherein no more than about 5% (w/w) of the acarabtinib maleate present in the dosage form degrades after six months of storage in suitable packaging at 40 ℃ and 75% relative humidity. In one aspect, the acaracinib maleate present in the dosage form does not degrade by more than about 3% (w/w) after storage in suitable packaging at 40 ℃ and 75% relative humidity for six months. In another aspect, no more than about 2% (w/w) degradation of the acaracinib maleate present in the dosage form occurs after six months storage in suitable packaging at 40 ℃ and 75% relative humidity. In another aspect, no more than about 1% (w/w) degradation of acarabtinib maleate present in the dosage form occurs after six months storage in blister packs at 40 ℃ and 75% relative humidity. In another aspect, no more than about 0.5% (w/w) degradation of acarabtinib maleate present in the dosage form occurs after six months storage in suitable packaging at 40 ℃ and 75% relative humidity. In one aspect, the package is a blister package, such as an aluminum blister. In another aspect, the package is a sealed HDPE bottle with desiccant. In another aspect, the degradation of acarabtinib maleate is analyzed using high performance liquid chromatography.
In some embodiments, the disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form is administered orally to a fasted human subject without an antacid with 100mgThe capsules (the composition of which corresponds to the contents of reference capsule C4 in table 6 of example 4) are substantially bioequivalent. In one aspect, the dosage form is based on 100mg { (R) } when administered orally to a fasting human subject who is not administered a gastric antacid>Capsule having a relative mean C of plasma acaracinib max 、AUC (0-t) And AUC (0-∞) Within a confidence interval of 80% to 125%. In another aspect, the dosage form is based on 100mg { (R) } when administered orally to a fasting human subject who is not administered a gastric antacid>Capsule with plasma acaracinib and its active metabolite ACP-5862 (namely 4- [ 8-amino-3-[4- (but-2-ynylamino) butanoyl group]Imidazo [1,5-a]Pyrazin-1-yl radicals]-N-pyridin-2-ylbenzamide) relative average C max 、AUC (0-t) And AUC (0-∞) Within a confidence interval of 80% to 125%.
In some embodiments, the disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form, when administered twice daily to a population of fasting human subjects, satisfies one or more of the following pharmacokinetic conditions for acarabetiib:
average C in a population of human subjects max Values from about 400ng/mL to about 900ng/mL;
mean AUC in a population of human subjects (0-24) A value of about 350ng hr/mL to about 1900ng hr/mL; and/or
Mean AUC in a population of human subjects (0-∞) Values are about 350 ng-hr/mL to about 1900 ng-hr/mL.
In one aspect, the dosage form is co-administered with a gastric acid reducing agent to a population of human subjects.
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 of at least about 90% in peripheral blood mononuclear cells 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 of at least about 95% in peripheral blood mononuclear cells 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.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form wherein the acaracinib maleate is present in an amount from about 15% to about 55% (free base equivalents) by weight of the dosage form. In one aspect, the acaracitinib maleate is present in an amount from about 25% to about 50% by weight of the dosage form. In another aspect, the acaracinib maleate is present in an amount from about 25% to about 45% by weight of the dosage form. In another aspect, the acaracitinib maleate monohydrate is present in an amount from about 25% to about 40% by weight of the dosage form.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein 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. One or more excipient interactions in a dosage form potentially affect the suitability of an excipient combination in a dosage form of the present disclosure. Thus, the selected combination of excipients preferably does not substantially affect the suitability of the dosage form for pharmacological use.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dose comprises at least one diluent, wherein the at least one diluent is present in an amount from about 10% to about 70% by weight of the dosage form. In one aspect, the at least one diluent is present in an amount from about 20% to about 70% by weight of the dosage form. In another aspect, the at least one diluent is present in an amount from about 30% to about 70% by weight of the dosage form. In another aspect, the at least one diluent is present in an amount from about 40% to about 70% by weight of the dosage form. In another aspect, the weight ratio of the acaracitinib maleate to the at least one diluent is about 1:3 to about 2:1. In another aspect, the weight ratio of acaracitinib maleate monohydrate to the at least one diluent is from about 1:1 to about 1:2.
When present, the selected diluent or diluents preferably do not affect the stability of the primary amine moiety of the acaracinib. In one aspect, the diluent does not readily react with the primary amine moieties in the maillard reaction. For example, the diluent is not a reducing sugar such as lactose. Furthermore, the one or more diluents preferably do not contain a maleic acid scavenger such as a metal salt. In one aspect, the one or more diluents do not comprise anhydrous dibasic calcium phosphate. Acceptable diluents include, for example, sugar alcohols (e.g., mannitol, sorbitol, maltitol, and xylitol), hydrolyzed starch, partially pregelatinized starch, and cellulose (e.g., microcrystalline cellulose and silicified microcrystalline cellulose), and combinations thereof (e.g., including mannitol and starch).
In some embodiments, the at least one diluent comprises a plastic diluent and a brittle diluent. A plastic diluent, such as microcrystalline cellulose, is a diluent that irreversibly deforms after exceeding the yield point during compression, resulting in a viscous flow of the granules and retaining deformation after removal of the compressive force. A brittle diluent, such as mannitol, will disintegrate during compression, creating a new surface for the particles to bind to. In one aspect, the dosage form comprises a total amount of plastic diluent and friable diluent from about 10% to about 70% by weight of the dosage form; wherein the plastic diluent is present in an amount from about 0% to about 70% by weight of the dosage form; the friable diluent is 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 will affect the tensile strength of the tablet. An excess of plastic diluent can weaken the tensile strength of the tablet. In one aspect, the w/w ratio of plastic diluent to brittle diluent in the dosage form is from about 0. In another aspect, the w/w ratio of plastic diluent to friable diluent in the dosage form is about 0 to about 100 to about 60, wherein the dosage form is a tablet having a tensile strength of at least 2.0 MPa.
In some embodiments, the at least one diluent comprises mannitol. In one aspect, mannitol is present in an amount of about 10% to about 70% by weight of the dosage form.
In some embodiments, the at least one diluent comprises microcrystalline cellulose. In one aspect, the microcrystalline cellulose is present in an amount from about 5% to about 50% by weight of the dosage form.
In some embodiments, the at least one diluent comprises mannitol and microcrystalline cellulose. In one aspect, mannitol is present in an amount of about 0% to about 70% by weight of the dosage form; wherein 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 from about 10% to about 70% by weight of the dosage form. In another aspect, the w/w ratio of mannitol to microcrystalline cellulose is from about 0 to about 100 to about 60. In another aspect, the w/w ratio of mannitol to microcrystalline cellulose in the dosage form is from about 0 to about 100 to about 60, wherein the dosage form is a tablet having a tensile strength of at least 2.0 MPa.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dose comprises at least one disintegrant and the at least one disintegrant is present in an amount of from about 0.5% to about 15% by weight of the tablet. In one aspect, the at least one disintegrant is present in an amount from about 1% to about 10% by weight of the tablet. In another aspect, the at least one disintegrant is present in an amount from about 2% to about 8% by weight of the tablet. In another aspect, the at least one disintegrant is present in an amount from about 3% to about 7% by weight of the tablet. In another aspect, the weight ratio of acamprovinib maleate (free base equivalent) to at least one disintegrant is from about 2:1 to about 15. In another aspect, the weight ratio of acaracitinib maleate to the at least one disintegrant is about 4:1 to about 10.
When present, the selected disintegrant or disintegrants preferably do not comprise an ionic disintegrant. In one aspect, the at least one disintegrant does not comprise sodium starch glycolate and/or croscarmellose sodium. In one aspect, the at least one disintegrant does not comprise sodium starch glycolate. In another aspect, the at least one disintegrant does not comprise croscarmellose sodium. Acceptable disintegrants include, for example, hydroxypropyl cellulose, corn starch, microcrystalline cellulose, crospovidone, and combinations thereof. In one aspect, the at least one disintegrant comprises hydroxypropyl cellulose. In another aspect, the at least one disintegrant comprises low-substituted hydroxypropyl cellulose.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dose comprises at least one lubricant and 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 from about 1% to about 4% by weight of the dosage form. In another aspect, the at least one lubricant is present in an amount from 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 from about 2% to about 3% by weight of the dosage form. In another aspect, the weight ratio of acaracinib maleate (free base equivalent) to the at least one lubricant is from about 20 to about 1. In another aspect, the weight ratio of acaracinib maleate to the at least one lubricant is from about 18 to about 1.
Acceptable lubricants include, for example, sodium stearyl fumarate, stearic acid, myristic acid, palmitic acid, sugar esters (e.g., sorbitan monostearate and sucrose monopalmitate), and combinations thereof. In another aspect, the at least one lubricant comprises sodium stearyl fumarate. Magnesium stearate is generally avoided as one or more of the lubricants.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form comprises:
acamprovinib maleate in an amount from about 15% to about 55% (free base equivalents) by weight of the dosage form;
at least one diluent in an amount from about 10% to about 70% by weight of the dosage form;
at least one disintegrant in an amount from about 0.5% to about 15% by weight of the dosage form; and
at least one lubricant in an amount from about 0.25% to about 4% by weight of the dosage form; and is
Wherein the sum of the amounts equals 100% of the total weight of the dosage form.
In one aspect, the dosage form consists essentially of the components described above. In a further aspect, the acamprovinib maleate is present as acamprovinib maleate monohydrate.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form comprises:
acaracitinib maleate monohydrate in an amount from about 20% to about 50% (free base equivalents) by weight of the dosage form;
at least one diluent in an amount from about 20% to about 70% by weight of the dosage form;
at least one disintegrant in an amount from about 1% to about 10% by weight of the dosage form; and
at least one lubricant in an amount from about 1% to about 4% by weight of the dosage form; and
wherein the sum of the amounts equals 100% of the total weight of the dosage form.
In one aspect, the dosage form consists essentially of the above-described components. In a further aspect, the acaracitinib maleate is present as acaracitinib maleate monohydrate.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form comprises:
acamprovinib maleate in an amount from about 25% to about 50% (free base equivalents) by weight of the dosage form;
at least one diluent in an amount from about 30% to about 70% by weight of the dosage form;
at least one disintegrant in an amount from about 2% to about 8% by weight of the dosage form; and
at least one lubricant in an amount from about 1.5% to about 3.5% by weight of the dosage form; and is
Wherein the sum of the amounts equals 100% of the total weight of the dosage form.
In one aspect, the dosage form consists essentially of the above-described components. In a further aspect, the acamprovinib maleate is present as acamprovinib maleate monohydrate.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form comprises:
acamprovinib maleate in an amount from about 25% to about 40% (free base equivalents) by weight of the dosage form;
at least one diluent in an amount from about 40% to about 70% by weight of the dosage form;
at least one disintegrant in an amount from about 3% to about 7% by weight of the dosage form; and
at least one lubricant in an amount from about 2% to about 3% by weight of the dosage form; and is
Wherein the sum of the amounts equals 100% of the total weight of the dosage form.
In one aspect, the dosage form consists essentially of the components described above. In a further aspect, the acaracitinib maleate is present as acaracitinib maleate monohydrate.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form comprises:
acamprovinib maleate in an amount from about 30% to about 35% (free base equivalents) 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 from 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 from about 1% to about 4% by weight of the dosage form; and is
Wherein the sum of the amounts equals 100% of the total weight of the dosage form.
In one aspect, the dosage form consists essentially of the above-described components. In a further aspect, the acaracitinib maleate is present as acaracitinib maleate monohydrate.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form wherein the acaracinib maleate has a D below about 500 microns (v,0.9) The value is obtained. In one aspect, the acaracitinib maleate has a D of less than about 450 microns (v,0.9) The value is obtained. In another aspect, the acaracitinib maleate has a D of less than about 400 microns (v,0.9) The value is obtained. In another aspect, the acaracitinib maleate has a D of less than about 350 microns (v,0.9) The value is obtained. In another aspect, the acaracitinib maleate has a D of less than about 300 microns (v,0.9) The value is obtained. In another aspect, the acaracitinib maleate has a D from about 20 microns to about 500 microns (v,0.9) The value is obtained. In thatIn another aspect, the acaracitinib maleate has a D of about 50 microns to about 450 microns (v,0.9) The value is obtained. In another aspect, the acaracitinib maleate has a D of about 75 microns to about 400 microns (v,0.9) The value is obtained. In another aspect, the acaracitinib maleate has a D from about 75 microns to about 350 microns (v,0.9) The value is obtained. In another aspect, the acaracitinib maleate has a D from about 100 microns to about 300 microns (v,0.9) The value is obtained.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form wherein the acaracinib maleate meets one or more of the following conditions: d (v,0.1) Value less than about 20 microns, D (v,0.5) A value of less than about 145 microns, and D (v,0.9) Values below about 330 microns. In another aspect, the acaracitinib maleate has a D of less than about 145 microns (v,0.5) Sum of values D less than about 330 microns (v,0.9) The value is obtained. In another aspect, the acaracitinib maleate has a D of less than about 20 microns (v,0.1) Value, D less than about 145 microns (v,0.5) Sum of values and D of less than about 330 microns (v,0.9) The value is obtained.
In some embodiments, the present disclosure relates to a solid pharmaceutical dosage form, wherein the dosage form is a capsule. In one aspect, the capsules are prepared by a process comprising roller compaction.
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 coating is a stabilizing film coating. In another aspect, the tablet is prepared by a process comprising direct compression. In another aspect, the tablets are 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 1.5MPa to about 5.0 MPa. In another aspect, the tablet has a tensile strength of about 2.0MPa to about 4.0 MPa. In another aspect, the tensile strength of the tablet does not decrease more than 10% from its initial tensile strength after six months of storage of the tablet in suitable packaging at 40 ℃ and 75% relative humidity. In another aspect, the tensile strength of the tablet does not decrease more than 8% from its initial tensile strength after six months of storage of the tablet in a suitable package at 40 ℃ and 75% relative humidity. In another aspect, the tensile strength of the tablet does not decrease more than 5% from its initial tensile strength after six months of storage of the tablet in suitable packaging at 40 ℃ and 75% relative humidity. In one aspect, the package is a blister package, such as an aluminum blister. In another aspect, the package is a sealed HDPE bottle with desiccant.
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 300mg to about 500 mg. In another aspect, the dosage form is a coated or uncoated tablet having a core weight of about 350mg to about 450 mg. In another aspect, the dosage form is a coated or uncoated tablet having a core weight of about 400 mg.
III.Method of treatment
The present disclosure also relates to a method of treating a BTK-mediated disorder in a subject, particularly a human subject suffering from or susceptible to a BTK-mediated disorder, the method comprising administering to the subject once or twice daily a solid pharmaceutical dosage form comprising acarabtinib maleate as described in any embodiment of the disclosure. In one aspect, the solid pharmaceutical dosage form comprising acarabtinib maleate is administered once daily. In another aspect, the solid pharmaceutical dosage form comprising acaracinib maleate is administered twice daily.
In one embodiment, the disclosure also relates to a method of treating a B-cell hematological malignancy in a subject, particularly a human subject suffering from or susceptible to a B-cell hematological malignancy, the method comprising administering to the subject once or twice daily a solid pharmaceutical dosage form comprising acarabtinib maleate as described in any embodiment of the disclosure. In one aspect, the solid pharmaceutical dosage form comprising acarabtinib maleate is administered once daily. In another aspect, the solid pharmaceutical dosage form comprising acaracinib maleate is administered twice daily.
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 lymphocytic leukemia (B-ALL), burkitt's lymphoma, waldenstrom's Macroglobulinemia (WM), multiple myeloma, myelodysplastic syndrome, and myelofibrosis.
In some embodiments, the B cell hematological malignancy is non-hodgkin 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.
In some embodiments, the B cell hematological malignancy is hodgkin's lymphoma.
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.
In some embodiments, the B cell hematological malignancy is mantle cell lymphoma. In one aspect, the mantle cell lymphoma is mantle zone lymphoma. Mantle cell lymphoma, on the other hand, 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 blastocyst-like mantle cell lymphoma.
In some embodiments, the B cell hematological malignancy is chronic lymphocytic leukemia.
In some embodiments, the B cell hematological malignancy is small lymphocytic leukemia.
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: new 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 a new 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. On the other hand, transformed diffuse large B-cell lymphoma is Richter syndrome (Richter syndrome).
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 and activated B cell diffuse large B cell lymphoma subtypes. In one aspect, the diffuse large B-cell lymphoma is relapsed/refractory germinal center B-cell diffuse large B-cell lymphoma. Diffuse large B-cell lymphoma, on the other hand, is relapsed/refractory activated B-cell diffuse large B-cell lymphoma.
In some embodiments, the B cell hematological malignancy is follicular lymphoma.
In some embodiments, the B cell hematological malignancy is waldenstrom's macroglobulinemia.
In some embodiments, the B cell hematological malignancy is B cell acute lymphoblastic leukemia. In one aspect, the B-cell acute lymphocytic leukemia is an early pre-B-cell acute lymphocytic leukemia. In another aspect, the B-cell acute lymphocytic leukemia is pre-B-cell acute lymphocytic leukemia. On the other hand, B-cell acute lymphocytic leukemia is mature B-cell acute lymphocytic leukemia.
In some embodiments, the B cell hematological malignancy is burkitt lymphoma. In one aspect, the burkitt's lymphoma is sporadic burkitt's lymphoma. Burkitt's lymphoma, on the other hand, is endemic burkitt's lymphoma. Burkitt's lymphoma, on the other hand, is a human immunodeficiency virus-associated burkitt's lymphoma.
The diagnosis of a particular B cell malignancy in a subject can be made according to accepted clinical practice. See, for example, the 2016 lymphoid tumor classification guideline set by the World Health Organization (WHO), or the national integrated cancer network (NCCN) non-hodgkin's lymphoma classification guideline.
In some embodiments, the human subject has previously received at least one prior chemoimmunotherapy for a B cell malignancy. In one aspect, prior chemoimmunotherapy comprises treatment with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). In another aspect, previous chemoimmunotherapy comprises treatment with fludarabine, cyclophosphamide and rituximab (FCR). In another aspect, prior chemoimmunotherapy comprises treatment with rituximab and Bendamustine (BR). In another aspect, prior chemoimmunotherapy comprises treatment with chlorambucil and obituzumab.
In some embodiments, the human subject has previously received treatment with a BTK inhibitor other than acartib (e.g., ibrutinib or zanubbrutinib).
In another embodiment, the present disclosure relates to the use of a solid pharmaceutical dosage form comprising acarabtinib maleate, as described in any embodiment of the present disclosure, for the treatment of a B-cell malignancy.
In another embodiment, the present disclosure relates to the use of a solid pharmaceutical dosage form comprising acarabtinib maleate, as described in any embodiment of the present disclosure, in the preparation of a medicament for the treatment of a B-cell malignancy.
In some embodiments, a solid pharmaceutical dosage form comprising acaracinib 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.
In some embodiments, the present disclosure relates to a method of improving the pharmacokinetics of orally administered alcanib in a subject suffering from or susceptible to a B cell hematological malignancy, the method comprising administering once daily (QD) or twice daily (BID) to the subject a solid pharmaceutical dosage form containing alcanib maleate as described in any embodiment of the present disclosure. In one aspect, the method improves and/or reduces intra-and/or inter-subject variability in acaracinib bioavailability. In another aspect, the method reduces acarabtinib pharmacokineticsIntra-subject and/or inter-subject variability. In another aspect, the method improves and/or reduces acarabtinib C max Intra-subject and/or inter-subject variability. In another aspect, the method improves and/or reduces acarabtinib T max Intra-subject and/or inter-subject variability. In another embodiment, the acaracinib AUC is improved and/or decreased (0-∞) Intra-subject and/or inter-subject variability.
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), the method comprising administering to the subject a solid pharmaceutical dosage form containing acarabtinib maleate as described in any embodiment of the disclosure.
In another embodiment, the present disclosure relates to the use of a solid pharmaceutical dosage form comprising acarabtinib maleate, as described in any embodiment of the present disclosure, in a human subject infected with SARS-CoV-2 and/or having a coronavirus disease 2019 (COVID-19).
In another embodiment, the present disclosure relates to the use of a solid pharmaceutical dosage form comprising acarabtinib maleate, as described in any embodiment of the present disclosure, in the preparation of a medicament for treating a human subject infected with SARS-CoV-2 and/or having a coronary virus disease 2019 (COVID-19).
The methods of the present disclosure also contemplate treatments comprising co-administering a solid pharmaceutical dosage form comprising acaracinib maleate as described in any embodiment of the present disclosure with one or more additional therapeutic agents. Thus, a dosage form of the present disclosure may 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 acaracinib maleate dosage forms of the present disclosure or sequentially with the acaracinib maleate dosage forms of the present disclosure. In one aspect, the therapeutic agent is an anti-CD 20 antibody. In another aspect, the anti-CD 20 antibody is selected from the group consisting of: rituximab, ocleilizumab, obituzumab, ofatumumab, titan-Ai Ruituo momab, tositumomab and ulituximab. In another aspect, the anti-CD 20 antibody is selected from the group consisting of: rituximab, obituzumab and ofatumumab. In another aspect, the anti-CD 20 antibody is rituximab. In another aspect, the anti-CD 20 antibody is obinutuzumab. In another aspect, the anti-CD 20 antibody is ofatumumab.
IV.Reagent kit
The present disclosure further relates in part to a kit comprising one or more solid pharmaceutical dosage forms comprising acarabtinib maleate as described in any embodiment of the present disclosure. The kit may optionally comprise one or more additional therapeutic agents and/or instructions for using the kit. Suitable packaging and additional articles of use are known in the art and may be included in the kit. The kit may be provided, sold and/or promoted to healthcare providers, including physicians, nurses, pharmacists, prescribing personnel, and the like.
In some embodiments, the kit comprises a semi-permeable container containing one or more solid pharmaceutical dosage forms comprising acaracinib maleate. In one aspect, the semi-permeable container is a blister pack.
In some embodiments, the kit comprises a substantially impermeable container containing one or more solid pharmaceutical dosage forms comprising acaracinib maleate. In one aspect, the impermeable container is a HDPE bottle with desiccant.
In some embodiments, the kit comprises a plurality of individual packages, each package comprising a daily dose of a solid pharmaceutical dosage form comprising acarabtinib maleate (e.g., a package comprising one or two solid dosage forms).
The above-described kit is preferably used for the treatment of a B cell malignancy as described in the present specification. For example, in one aspect, the B cell malignancy is non-hodgkin's lymphoma. In another aspect, the B cell malignancy is mantle cell lymphoma. In another aspect, the B cell malignancy is chronic lymphocytic leukemia. In another aspect, the B cell malignancy is a small lymphocytic leukemia. In another aspect, the B cell malignancy is diffuse large B cell lymphoma.
In another embodiment, the above-described kit is used to treat a human subject infected with SARS-CoV-2 and/or having coronavirus disease 2019 (COVID-19).
V.Preparation method
The present disclosure also relates to methods of making solid pharmaceutical dosage forms comprising acaracinib maleate described in the present disclosure, including those methods described in the examples below. In general, these dosage forms can be prepared using, for example and without limitation, the following techniques: direct mixing, dry granulation (roller compaction), wet granulation (high shear granulation), milling or sieving, drying (if wet granulation is used), compression, and optionally coating.
VI.Product technology
The present disclosure also relates to solid pharmaceutical dosage forms comprising acaracinib maleate prepared according to any of the methods described in the present disclosure, including the methods described in the examples below.
VII.Examples of the invention
Example 1: evaluation of acarabtinib salts
1.Dissolution study
The phosphate, oxalate and maleate salts of acaracinib were evaluated using a two-stage in vitro dissolution method called the pH shift method. The starting medium is deionized water or simulated gastric fluid containing hydrochloric acid and sodium chloride, adjusted to a pH of 1.8. After the salt had been left in the initial medium for 30 minutes, the medium was then exchanged for FaSSIF-V2 medium by adding a double concentration concentrate, the final pH being 6.5. The FaSSIF-V2 medium contains a sodium phosphate buffer containing sodium chloride, sodium taurocholate and lecithin. Dissolution testing was performed as follows: the procedure was performed using USP dissolution apparatus 2 (paddle) at 37 ± 0.5 ℃ at 50RPM in 250mL of medium for the first 30 minutes and then 500mL of medium after the transition. Samples from the dissolution medium were taken from the aqueous phase at predetermined time points and analyzed by HPLC. FIGS. 2 and 3 show the dissolution profiles of three salts in simulated gastric fluid/FaSSIF-V2 medium and deionized water/FaSSIF-V2 medium, respectively. While these three salts exhibit roughly similar performance in low pH simulated gastric fluid media, the maleate salt exhibits significantly reduced dissolution in neutral aqueous media relative to the oxalate and phosphate salts.
2.Study of physical Properties
The physical properties of the phosphate, oxalate and maleate salts of acaracinib, including physical stability, crystallinity and particle habit were investigated.
Solid state analysis of phosphate shows complex hydrate behavior at ambient conditions, where the solids will shift between hydrated forms, one crystalline form converting to a higher hydrate crystalline form at a relative humidity ("RH") above 20% RH, as evidenced by the dynamic vapor sorption ("DVS") graph in fig. 4. Thermogravimetric analysis ("TGA") showed that the higher hydrates were physically unstable and rapidly dehydrated in less than 10 minutes in an open pan under isothermal conditions at 40 ℃, as shown in figure 5. Standard TGA further indicates that phosphate batches are generally heterogeneous in water content and therefore in physical form. X-ray powder diffraction ("XRPD") demonstrated that both forms could be identified, as shown in figure 6.
Oxalate also exhibits complex hydrate behavior. TGA indicates that the hydrate is very unstable as demonstrated in figure 7. The half-life of water loss was 4 minutes and the total weight loss was 3.2% w/w under isothermal TGA conditions of 35 ℃. The water loss corresponds to about one mole of water per mole of oxalate. As shown in fig. 8, DVS shows the conversion of one crystalline form to a higher hydrate crystalline form at ambient humidity. Oxalate demonstrated very fine needle habits when analyzed by light microscopy.
The maleate is isolated as the monohydrate. Although isothermal TGA at 50 ℃ indicates dehydration of the monohydrate as shown in figure 9A, the rate of dehydration is slower than that of the phosphate or oxalate at lower temperatures of 40 ℃ and 35 ℃, respectively. Figure 9B is a TGA plot performed under an alternative set of conditions. The DVS plot of the maleate salt in fig. 10A shows that the% w/w water change is less than that observed with the phosphate or oxalate salt over the entire humidity range. Figure 10B is a DVS plot of a higher quality maleate sample. The maleate salt has a large crystal habit and is in the form of a mass.
Although the dissolution of phosphates and oxalates in neutral aqueous media is significantly better than maleates, the physical properties of phosphates and oxalates present a greater challenge in developing pharmaceutically acceptable formulations comprising acarabtinib salts.
3.Dissolution of micronized maleate salts
In view of formulation challenges associated with the physical properties of phosphate and oxalate, after undergoing particle size reduction, maleate was retested in the pH change dissolution method previously described. Micronized maleate batches tested and D of the unmilled maleate batches (v,0.9) Typical average values of the particle size distribution are usually about 18 μm and 446 μm, respectively. Using the same process conditions as previously described, micronized maleate samples were tested and showed significantly improved dissolution profiles (and to a greater extent than would be expected by a person skilled in the art) relative to the unmilled maleate samples. FIGS. 11 and 12 show the dissolution profiles of micronized and unmilled maleate in simulated gastric fluid/FaSSIF-V2 medium and deionized water/FaSSIF-V2 medium, respectively.
Example 2: evaluation of acarabtinib maleate solubility
The solubility of acaracitinib maleate was measured in unbuffered medium and found to be about 3mg/mL at pH 4, the calculated pH max Was 4.11. It was further determined that acartib maleate buffered to a surface pH value between 3.8 and 5 in unbuffered media with an initial pH above pH 4 and up to about pH 11, and that the solubility of acartib maleate in unbuffered media from pH 4 to pH 11 was maintained at about 3mg/mL. In contrast, as the pH approaches pH6, the solubility of acaracinib free base in the unbuffered medium decreases to less than about 0.1mg/mL.
Furthermore, the solubility of acaracitinib maleate is measured in a buffer solution representing the medium for dissolving the acaracinib maleate tablets. It was found that the final pH value is also affected by the presence of acamprovine maleate and that, depending on the buffer used, acamprovine maleate is able to be supersaturated compared to the free base at the same final pH value or exhibits a solubility value close to that of the free base at the same final pH value. For example, acarabtinib maleate is supersaturated in pH 4.5 acetate buffer and has a solubility significantly higher than the solubility of the free base in pH 4.5. In phosphate buffer, the phosphate concentration and final pH adjustment controls the final pH and final solubility of acaracinib maleate, but the values observed under all conditions are close to the values of acaracinib free base at the same final pH. Figure 13 depicts the solubility of acamprovinib maleate and acamprovinib free base in various buffer solutions compared to final pH values.
Example 3: physicochemical characteristics of acaracitinib maleate monohydrate
Selected physicochemical properties of acaracitinib maleate monohydrate were determined and reported in table 2 below.
TABLE 2
/>
Example 4: acarabtinib maleate tablet
Tablets comprising acaracinib monohydrate and various excipients were prepared by direct compression or roller compaction and are further described below. The directly compressed tablets were uncoated and the rolled tablets were film coated. All tablets prepared contained a unit dose of about 100mg equivalent of acamprovinib maleate monohydrate.
A.Direct compression
Tablets having the compositions listed in tables 3 and 4 were prepared by direct compression. All components except the lubricant were mixed prior to compression, then screened through a screen, and then mixed again. The screened lubricant is added to the mixture and then lubricated by further mixing. The tablets are compressed using a suitable tablet press and tooling appropriate to the target tablet weight. In the event that additional lubrication of the tablet is required (i.e. punch drop or sticking is observed), additional lubricant is applied outside the tablet die.
TABLE 3
/>
a Micronized acaracitinib maleate
b Acarabtinib maleate particle size, D (v,0.9) ≈70μm
B.Rolled tablets
Tablets having the composition listed in table 5 were prepared by roller compaction. All components except the lubricant were mixed. The intra-granular fraction of the lubricant is screened and then added to the mixture, which is then lubricated by further mixing. The lubricated mixture was rolled into a ribbon shape and subsequently ground into granules. The extra-granular portion of the lubricant is screened and then added to the granules, which are then lubricated by further mixing. Tablet cores were compressed using a 13x7.5mm oval tablet tool to target compression weights and forces of 400mg and 14 kN. The resulting cores are film coated with a 3% to 4% weight gain of the coating suspension.
TABLE 5
a Acaracib maleate particle size, D (v,0.9) ≈260μm
b Acaracib maleate particle size, D (v,0.9) ≈198μm
c Acaracib maleate particle size, D (v,0.9) ≈270μm
d Acarabtinib maleate particle size, 50 (v,0.9) 70 μm and D (v,0.9) ≈150μm
e Acarabtinib maleate particle size, D (v,0.9) ≈70μm
C.Rolled capsules
In addition to the above tablets, reference capsules containing acaracinib free base and having the composition listed in table 6 were prepared and used in the following examples. All components except the lubricant were mixed, then sieved through a sieve, and then mixed again. The screened lubricant is added to the mixture and then lubricated by further mixing. The lubricated mixture is fed into a roller press and the resulting tape is subsequently ground to produce particles suitable for encapsulation. The screened extra-granular lubricant was mixed with the acaracinib granules, lubricated, and filled into a No. 1 hard gelatin capsule using a sealer to achieve a target fill weight of 240mg (i.e., 100mg of acaracinib free base).
TABLE 6
a Acaracinib free base particle size, D (v,0.9) ≈365μm
b Acaracinib free base particle size, D (v,0.9) ≈392μm
c Acaracinib free base particle size, D (v,0.9) ≈394μm
d Acaracinib free base particle size, D (v,0.9) ≈377μm
D.Film coated tablet T21
Another example of a film-coated dosage form (T21) is described in table 7 below.
TABLE 7
*100mg free base equivalent.
Example 5: evaluation of in vitro dissolution profiles
In vitro dissolution studies were performed to evaluate the dissolution profile of the acarabtinib maleate formulation at low pH conditions and elevated pH conditions. The pH conditions are selected to mimic gastric pH conditions, wherein the tablets are administered alone (low pH conditions) or co-administered with a proton pump inhibitor or acid-reducing agent (elevated pH conditions). Details of the dissolution study are provided below.
1.Low pH 0.1N HCL dissolution test
Fig. 14 shows the dissolution profiles obtained from the low pH test of the acartinib maleate tablets T16, T17 and T18 and the acartinib free base capsule C1 under sink conditions. Dissolution testing was performed in 900mL of dissolution medium containing 0.1N hydrochloric acid and using USP dissolution apparatus 2 (paddle type) (run at 37. + -. 0.5 ℃ C. At 50 RPM). Samples of the dissolution medium were taken from the aqueous phase at predetermined time points and determined by HPLC or UV/visible spectroscopy. The results show that the acaracinib maleate tablets and the acaracinib free base capsules have similar dissolution profiles under low pH conditions.
2.Neutral pH Low ionic Strength 5mM phosphate pH6.8 dissolution test
Fig. 15 shows the dissolution profiles obtained from the neutral pH low ionic strength test of acaracinib maleate tablets T16, T17 and T18 under sink conditions. Dissolution testing was performed in 900mL dissolution medium containing 5mM sodium phosphate (pH adjusted to 6.8) and using USP dissolution apparatus 2 (paddle) (operating at 75RPM at 37. + -. 0.5 ℃). Samples in the dissolution medium were taken from the aqueous phase at predetermined time points and determined by UV/visible spectroscopy. The results show that these acaracinib maleate tablets substantially retain the dissolution profile shown at low pH when tested under elevated pH conditions.
3.Neutral pH high ionic Strength 50mM phosphate pH6.8 dissolution test
Figure 16 shows the dissolution profiles obtained from the neutral pH high ionic strength test of acaracinib maleate tablet T13 and acaracinib free base capsule C2. Dissolution testing was performed in 900mL dissolution medium containing 50mM sodium phosphate (pH adjusted to 6.8) and using USP dissolution apparatus 2 (paddle) (operating at 75RPM at 37. + -. 0.5 ℃). Samples from the dissolution medium were taken from the aqueous phase at predetermined time points and analyzed by HPLC. The results show improved dissolution profiles of the acaracinib maleate tablets at elevated pH relative to the acaracinib free base capsules.
4.Water dissolution test
Figure 17 shows the dissolution profiles of acaracinib maleate tablets T1 and acaracinib free base capsules C1 obtained from neutral media without buffer capacity (i.e. stomach conditioned similarly to proton pump inhibitor treatment). Dissolution testing was performed in 300mL of dissolution medium containing deionized water and using USP dissolution apparatus 2 (paddle) (run at 37 ± 0.5 ℃ and 50 RPM). Samples from the dissolution medium were taken from the aqueous phase at predetermined time points and analyzed by HPLC.
Fig. 18 shows the dissolution profile of acaracinib maleate tablets T13 and acaracinib free base capsules C1 obtained from neutral medium without buffer capacity. Dissolution testing of tablet T13 was performed as follows: the dissolution medium was run at 75RPM and 37 ± 0.5 ℃ using USP dissolution apparatus 2 (paddle) in a volume of 900mL dissolution medium containing deionized water and compared to the reference tablet C1 tested at 300mL and 50 RPM. Samples from the dissolution medium were taken from the aqueous phase at predetermined time points and analyzed by HPLC.
The results in figures 17 and 18 show improved dissolution profiles of acaracinib maleate tablets at elevated pH relative to acaracinib free base capsules.
5.Biologically relevant medium testing
Dissolution of the acarabtinib maleate tablet T19 was evaluated under gastric conditions associated with an acidic gastric compartment and under gastric conditions associated with administration of a proton pump inhibitor or acid reducer combination. The starting medium used was either simulated gastric fluid containing hydrochloric Acid and sodium chloride and adjusted to a pH of 1.8, or a low buffer capacity medium designed for repeated proton pump inhibitor treated stomach (see Segregur D., et al, "Impact of Acid-Reducing Agents on gastric Physiology and Design of Bioprecise disorders Tests to Reflect the effects of Acid scavengers on Gastrointestinal Physiology and the Design of biologically relevant Dissolution Tests reflecting These Changes ]," J.Pharm.Sci. [ J.Pharmacology ],108 (11): 2461-3477 (2019)). PPI buffers are maleate based and contain sodium chloride adjusted to pH6. After tablet T19 had been present in the initial medium for 30 minutes, the medium was converted to FaSSIF-V2 medium by adding a double concentration of concentrate, with a final pH of 6.5. The FaSSIF-V2 medium contains a sodium phosphate buffer containing sodium chloride, sodium taurocholate and lecithin. Dissolution testing was performed as follows: the process was carried out using USP dissolver 2 (paddle) operating at 37. + -. 0.5 ℃ at 75RPM in 250mL for the first 30 minutes and then in 500mL after conversion. Samples from the dissolution medium were taken from the aqueous phase at predetermined time points and analyzed by HPLC. After the pH of both starting media had been converted to FaSSIF-V2, acarabtinib (at 100mg free base equivalent dose) did not precipitate and supersaturate for at least another 90 minutes, as demonstrated in figure 19.
In a separate dissolution test, the acaracinib maleate tablet T19 and the acaracinib free base capsule C3 were evaluated under the same pH variation conditions as described above, using simulated gastric fluid pH 1.8 as the initial medium. The results reported in figure 20 show that the maleate tablets have in vitro dissolution properties under biologically relevant conditions corresponding to fasted state stomach, comparable to the free base capsules.
In general, the results of in vitro dissolution testing indicate that the dissolution profiles of acartinib maleate tablets tested at low pH and elevated pH conditions are substantially comparable, further indicating that such tablets are bioequivalent when administered alone or in combination with a proton pump inhibitor or acid reducer.
Example 6: evaluation in TIM-1 model
A study was conducted using the TNO TIM-1 (TIM-1) system, an important tool in testing cascades used to establish a mechanical understanding of the performance of in vitro products and to demonstrate the clinical relevance of selected in vitro methods. The TIM-1 system has previously been described in detail in the literature. See, e.g., barker, R., et al, "Application and validation of an advanced gastrointestinal in vitro model for the evaluation of drug performance in drug development ]," J.pharm.Sci. [ J.Pharmacology ], vol.103, no. 11, no. 15, pp.3704-3712 (9 months 2014). The TIM-1 system is a multi-compartmental, dynamic system that utilizes relevant mediators, volumes, pH, and fluid dynamics in vivo to simulate conditions in the upper GI tract of an adult. The system also simulates an absorptive sink (adsorbent sink) by hollow fiber ultrafiltration. The volume, medium composition, rate of emptying, temperature and pH are all dynamically controlled by a computer, allowing the definition of various subject physiology, such as fasting, fed or other various more complex disease states.
More specifically, the study was conducted in a TIM-1 system to evaluate the relative performance of acarabtinib maleate tablets T19 and acarabtinib free base capsules C2, under gastric conditions associated with an acidic gastric compartment and also under gastric conditions associated with co-administration of a proton pump inhibitor or acid-reducing agent. The conditions selected represent humans with gastric pH values of 2 and 6. Gastric emptying rate was set to "fast" mode to represent the most challenging condition of the formulation from the point of view of pH changeThe method is described. This means that the gastric compartment t 1/2 This is typically 15 minutes in a fasted adult. Test items were added to the TIM-1 system and the selected protocol was run for 300 minutes. The system was then run automatically, and samples from the absorption compartment were collected every 60 minutes and assayed by HPLC.
Figure 21 shows that performance of the acaracinib maleate tablets is comparable to that of the acaracinib free base capsules under low pH (pH 2) conditions. It also shows that the performance of the acaracinib maleate tablets is not affected by high pH (pH 6) conditions and does not precipitate due to pH changes that occur when the stomach empties into the duodenum.
Example 7: effect of particle size and drug load on dissolution Rate
A study was conducted to evaluate the effect of drug substance particle size and drug substance loading on the in vitro dissolution of acaracinib maleate tablets. The tablets evaluated contained acaracinib maleate (100 mg free base equivalent), D (v,0.9) Particle size (measured by laser diffraction) ranged from 16 microns to 500 microns with drug loading of 26 or 43 wt%. Dissolution testing was performed in 900mL of 5mm sodium phosphate buffer medium using a USP2 dissolution apparatus (paddle) operating at 75RPM and 37 ± 0.5 ℃.
Acaracinib maleate tablets T9, T10, T11, T12, T13, T14 and T15 were evaluated in the study. The drug substance particle size and drug loading for each tablet is summarized in table 8 below.
TABLE 8
Figure 22 additionally shows the particle size distribution of the acaracinib maleate tablets T10, T11, T13 and T15. Tablets evaluated for the effect of drug loading were acaracinib maleate tablets T10, T11, T13 and T15 (drug loading of 26 wt%) and acaracinib maleate tablets T9, T2 and T14 (drug loading of 43 wt%), respectively. FIGS. 23 and 24 showResults for the catamenial maleate tablets T10, T11, T13 and T15 (drug loading of 26 wt%) and the acartitinib maleate tablets T9, T12 and T14 (drug loading of 43 wt%). The tablet dissolution rate generally decreases with increasing acaracib maleate particle size, although this observation is not applicable to tablets with the finest acaracib particle size (T11). One possible explanation for the difference in tablet T11 results is that the very fast dissolution rate at the initial time point is reduced due to the lack of drug wetting. Having a D of from 70 to 500 μm under the test conditions (v,0.9) The in vitro dissolution rates of the acaracitinib maleate tablets with a particle size distribution within the range are relatively consistent when the drug load is increased from 26% to 43% by weight.
Example 8: gastroplus modeling and simulation of acarabtinib exposure
Software modeling and simulation studies were performed to predict acartinib exposure in human subjects following administration of the acartinib maleate tablets of example 7 (i.e., T10, T11, T13, and T15). The batch-specific drug product particle size distribution ("P-PSD") for each tablet was derived using the tablet dissolution rate data obtained in example 7 according to the method described by Pepin et al (Pepin, x.j.h., et al, "bright in vitro dissolution and in vivo exposure for acalbutinib. Part i.mechanical dissolution to derivative a P-PSD for PBPK model input [ bridge in vitro dissolution and in vivo exposure of acalbutinib. Part I. Mechanism of drug product dissolution modeling to derive P-PSD for PBPK model input ]," eur.j.pharm.biopharmam. [ european journal of drugs and biopharmaceuticals ], 142-421-434 (2019)). The derived P-PSD was then used as input to the PBPK model described by Pepin et al (Pepin, X.J.H., et al, "Bridging in vitro dissolution and in vivo exposure for acalkastic PBPK model for IR formation compliance, proton pump inhibitor drugs interactions, and administration with acidic fluids [ bridge in vitro dissolution and in vivo exposure of acarabtinib ], part II. Mechanism PBPK model for IR formulation comparison, proton pump inhibitor drug interaction, and acid juice administration ]," Eur.J.Pharm.and Biorm. European drug and biologies, 142, 2019).
Simulations predict that 100mg free base equivalent T10, T11, T13 and T15 tablets all have an average AUC and C with acaracinib free base reference capsule C4 under acidic gastric conditions max Mean AUC and C of comparable values max The value is obtained. Table 9 below summarizes the calculated mean exposure values for the acaracinib maleate tablets and the ratio of these calculated values to the corresponding values for the acaracinib free base reference capsules. The exposure rate of the T11 tablet approaches the lower limit of bioequivalence, probably due to the slower dissolution rate associated with the wettability problem.
TABLE 9
Similar simulations predict that 100mg free base equivalent T10, T11, T13 and T15 tablets have mean AUC and C under neutral to acidic gastric conditions max Mean AUC and C of values over the pH range relative to acaracinib free base reference capsule C4 over the same pH range max The values are substantially maintained. The simulations support the following conclusions: the effect of the acid reducing agent on the acaracinib exposure can be significantly reduced relative to the acaracinib free base reference capsule C4, and the acaracinib maleate tablet maintains bioequivalence over an acidic to neutral pH range. Table 10 below summarizes the calculated mean exposure values for the acaracinib maleate tablets and the ratio of these calculated values to the corresponding values for the acaracinib free base reference capsules.
Watch 10
/>
Example 9: in vivo dog study
An in vivo study was performed to evaluate the co-administration of acartinib maleate and omeprazole relative to the co-administration of acartinib free base and omeprazole in a dog model. In this study, non-naive beagle dogs were dosed with capsules containing 100mg of acaracinib free base, with and without 10mg of omeprazole pretreatment, and the acaracinib AUC was measured (0-24) The value is obtained. In addition, after an appropriate washout period, the same dogs were given capsule size 13 containing a binary mixture of acaracinib maleate (100 mg equivalent) and 200mg microcrystalline cellulose, with and without omeprazole pretreatment, and the acaracinib AUC was measured (0-24) The value is obtained. The results of the study are shown in FIG. 25. The exposure of the acaracinib maleate capsules (100 mg free base equivalent) when administered with omeprazole pretreatment was comparable to that of the acaracinib free base capsules when not administered with omeprazole pretreatment.
Example 10: evaluation of excipients and combinations of excipients
A study was conducted to evaluate the suitability of certain excipients and excipient combinations in formulating acaracinib maleate dosage forms.
A.Disintegrating agent
A binary mixture of disintegrant and acaracinib maleate (1:5 ratio) was prepared and evaluated in an in vitro dissolution test. The binary mixture and maleate control were dissolved in 250mL of deionized water using a USP2 dissolution apparatus (paddle) at 37 ± 0.5 ℃ and 75 RPM. After the 120 minute time point, the paddle speed was increased to 250RPM, and after 135 minutes the pH was adjusted to pH 1.8-2 to increase solubility to determine if any undissolved material remained. The binary mixtures tested were sodium starch glycolate/acaracinib maleate (1:5 ratio), croscarmellose sodium/acaracinib maleate (1:5 ratio), and low substituted hydroxypropyl cellulose/acaracinib maleate (1:5 ratio).
The results are shown in FIG. 26. Only the acaracinib maleate control and the low substituted hydroxypropyl cellulose/acaracinib maleate (1:5 ratio) mixture did not significantly increase in dissolution upon increased paddle speed or addition of acid, indicating that complete dissolution had been achieved. For the croscarmellose sodium/acartinib maleate (1:5 ratio) mixture and the croscarmellose sodium/acartinib maleate (1:5 ratio) mixture, showed significantly increased dissolution after acid adjustment and indicated that complete release at higher pH levels may be a problem and that excipient/drug interactions occurred, which may be caused by the conversion of acartinib maleate to a less soluble form (such as the free base).
B.Lubricant agent
A binary mixture of lubricant and acarabtinib maleate (1. The binary mixtures tested were glyceryl dibehenate/acaracinib maleate (1.
The results are shown in FIG. 27. The dissolution of the acaracinib maleate control, the glyceryl dibehenate/acaracinib maleate (1. For the magnesium stearate/acaracinib maleate (1. Furthermore, when evaluating binary compacts of magnesium stearate and acaracinib maleate, these binary compacts show an increase in the extent of degradation of acaracinib compared to acaracinib maleate alone.
C.Diluent
Directly compressed tablet cores containing diluent, disintegrant, lubricant and acarabtinib maleate were prepared under the same conditions as described above for the disintegrant mixtures and evaluated in an in vitro dissolution test. Each tablet core contains microcrystalline cellulose/mannitol or microcrystalline cellulose/anhydrous dibasic calcium phosphate/mannitol as a diluent. The particular tablet cores tested contained (1) microcrystalline cellulose, anhydrous dibasic calcium phosphate, mannitol, low substituted hydroxypropyl cellulose, magnesium stearate and acartib maleate (T2), (2) microcrystalline cellulose, mannitol, low substituted hydroxypropyl cellulose, magnesium stearate and acartib maleate (T3), (3) microcrystalline cellulose, anhydrous dibasic calcium phosphate, mannitol, low substituted hydroxypropyl cellulose, sodium stearyl fumarate, and acartib maleate (T6), (4) microcrystalline cellulose, mannitol, low substituted hydroxypropyl cellulose, sodium stearyl fumarate, and acartib maleate (T8), (5) microcrystalline cellulose, anhydrous dibasic calcium phosphate, mannitol, low substituted hydroxypropyl cellulose, glyceryl dibehenate, and acartib maleate (T4), or (6) microcrystalline cellulose, mannitol, low substituted hydroxypropyl cellulose, glyceryl dibehenate, and acartib maleate (T5).
The results are shown in fig. 28 (cores T2 and T3), fig. 29 (cores T6 and T8) and fig. 30 (cores T4 and T5). For all mixtures tested, the presence of anhydrous dibasic calcium phosphate resulted in a greater increase in dissolution upon acid conditioning, indicating that anhydrous dibasic calcium phosphate interacted with acaracinib maleate. In contrast, no significant increase was observed for the mixture without anhydrous dibasic calcium phosphate. Furthermore, when evaluating binary compactates of anhydrous dibasic calcium phosphate and acaracinib maleate, these binary compactates show an increase in the extent of acaracinib degradation compared to acaracinib maleate alone.
Example 11: evaluation of stability of acarabtinib maleate tablets
A.Tablet T19 stability
A stability study was conducted to evaluate acarabtinib maleate tablets (T19) under open storage conditions and when provided in the following three package forms:
bulk packaging: laminated aluminum foil bag, 4 layers, tearable-185x 280mm (60 pieces per bag)
HPDE bottle-110 mL induction sealed, 1g silica gel desiccant canister (60 tablets per bottle)
HPDE bottle-110 mL induction sealed, 2g silica gel desiccant canister (60 tablets per bottle)
The storage conditions studied in the stability studies are detailed in table 11 below.
TABLE 11
| Condition | Last time point |
| 25℃/60％RH | 156 weeks |
| 30℃/75％RH | 156 weeks |
| Light exposure | 10 days |
| 40℃/75％RH | For 26 weeks |
| 30 ℃/75% RH (open) | 4 weeks |
| 40 ℃/75% RH (open)Put) | 4 weeks |
| 50℃ | 13 weeks |
By the 26 week time point, the following data were obtained:
explanation of: the physical appearance of any of the samples did not change.
Measurement of: no trend was observed in the analytical data of any of the test samples.
Organic impurities:
o for samples stored in suitable packaging (HDPE bottles with desiccant or aluminum bulk bags), the impurity levels meet the specification limits of 0.7% for the qualified impurity NMT and 0.2% for the unqualified impurity NMT.
o results in a level of 4- {2- [ (2S) -1- (2-butynoyl) -2-pyrrolidinyl ] -5-carbamimidoyl-1H-imidazol-4-yl } -N- (2-pyridinyl) benzamide exceeding the specification limit of NMT 0.2% after storage for 4 weeks at 40 ℃/75% RH. All other impurities meet the specification limit of qualified NMT 0.7% and unqualified NMT 0.2%.
Enantiomeric purity: all samples met the criteria of the method (. Gtoreq.99.6%) at both the initial and 26 week time points.
Dissolution (0.1N HCl): no trend was observed in any of the samples. All samples met the specification requirements (Q =80% at 20 minutes).
Dissolution (pH 6.8): no trend was observed in any of the samples. All samples met Q =80% at 20 minutes.
Water content: no tendency was observed in any of the samples stored with the desiccant or bulk package. The samples stored open all showed an increase in water content at 4 weeks, with the largest increase occurring in the 40 ℃/75% RH sample.
Shui Huodu: no trend was observed in the results.
Microbiological quality: all results were in compliance with the specification (Pharm Eur/USP).
Based on the generated data, aluminum bulk bags were deemed suitable to ensure proper bulk shelf life, and HDPE bottles containing desiccants were deemed suitable to ensure proper shelf life of the acarabtinib maleate film coated tablets tested.
B.Additional stability evaluation
A stability study was conducted to evaluate the chemical stability of acaracinib maleate tablets T2 and T3, and the following general observations were made:
the presence of anhydrous dibasic calcium phosphate promoted the formation of 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] -imidazo [1,5-a ] -pyrazin-1-yl } -N- (2-pyridyl) -benzamide and the RRT was 0.05.
The presence of magnesium stearate promoted the formation of 4- {2- [ (2S) -1- (2-butynoyl) -2-pyrrolidinyl ] -5-carbamimidoyl-1H-imidazol-4-yl } -N- (2-pyridyl) -benzamide and an RRT of 0.82.
The presence of microcrystalline cellulose promoted the formation of 4- {3- [ (2S) -1-acetoacetyl-2-pyrrolidinyl ] -8-aminoimidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide with an RRT of 0.82 and an RRT of 0.05.
Limited stability studies with limited data evaluation were performed on acaracinib maleate tablets T7 and T15 and the following observations were made:
the major degradation products were 4- {3- [ (2S) -1-acetoacetyl-2-pyrrolidinyl ] -8-aminoimidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide, RRT 0.82, and 4- {2- [ (2S) -1- (2-butynoyl) -2-pyrrolidinyl ] -5-carbamimidoyl-1H-imidazol-4-yl } -N- (2-pyridyl) -benzamide.
The increase in levels of 4- {3- [ (2S) -1-acetoacetyl-2-pyrrolidinyl ] -8-aminoimidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridinyl) benzamide (RRT 0.82) is higher than observed for acarabinib maleate tablets T2 and T3.
Humidity appears to have a significant effect on the formation of RRT 0.82, but may be controlled by suitable packaging.
Example 12: preparation of acaracitinib maleate
A.Conversion of acaracitinib free base to acaracinib maleate
Acarabtinib (18kg, 1.0 molar equivalent) in tetrahydrofuran (162l, 9.0 rel vol) and water (9l, 0.5 rel vol) was heated to 50 ℃ and filtered. Tetrahydrofuran (9L, 0.5 relative volume) was used as a line wash. Maleic acid (5kg, 1.1 molar equivalents) in tetrahydrofuran (68l, 3.75 rel vol) was added at 50 ℃ followed by a tetrahydrofuran (5l, 0.25 rel vol) line wash. The mixture was seeded with acaracinib maleate (18mg, 0.001 relative weight), held at 50 ℃ for 1 hour, then cooled to 20 ℃ over 1 hour and held for 1 hour, and then recycled through the wet mill to achieve the desired particle size distribution. The product was then filtered and washed with tetrahydrofuran (36l, 2.0 relative volume) and then dried at 40 ℃ by a stream of nitrogen (> 20% relative humidity) to give acarabinib maleate as a monohydrate (20.4 kg, 88%).
4- { 8-amino-3- [ (2S) -2-pyrrolidinyl]Imidazo [1,5-a]Pyrazin-1-yl } -N- (2-pyridyl) -
Conversion of benzamide to acaracitinib maleate
In another method of preparing acaracinib maleate, the maleate is prepared without intervening isolation of the acaracinib free base. To a mixture of 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) -benzamide (15.0 g,1.0 molar equivalent) and triethylamine (13.2ml, 2.6 molar equivalent) in tetrahydrofuran (80ml, 5.3 relative volume) was added 2-butyric acid (3.3g, 1.1 molar equivalent) in tetrahydrofuran (15ml, 1.0 relative volume) (over 1 hour), and after 8 minutes, propylphosphonic anhydride (53 w/w in ethyl acetate) (23.7g, 1.1 molar equivalent) (over 1 hour) in tetrahydrofuran (15ml, 1.0 relative volume) was simultaneously added. The mixture was stirred until the reaction was complete. The mixture was quenched with water (30mL, 2.0 relative volumes), the aqueous phase separated and discarded. The remaining organic phase was screened through a filter with a line wash of tetrahydrofuran (7ml, 0.5 rel vol). The mixture was then heated to 50 ℃ and treated with maleic acid (8g, 1.9 molar equivalent) in tetrahydrofuran (59mL, 3.9 relative volume). The mixture was seeded with acaracinib maleate (15mg, 0.001 relative weight), then cooled to 20 ℃ over 5 hours, filtered, washed three times with ethanol (30ml, 2.0 relative volume), then washed with tert-butyl methyl ether (58ml, 3.9 relative volume), then blotted on the filter for 30 minutes to give acaracinib maleate as the monohydrate (1lg, 74%).
Analysis of the product of method B above indicated the presence of the impurity (2Z) -4- [ (2S) -2- { 8-amino-1- [4- (2-pyridylcarbamoyl) phenyl ] imidazo [1,5-a ] pyrazin-3-yl } -1-pyrrolidinyl ] -4-oxo-2-butenoic acid which was not observed in the product of method A. The amount of such impurities present may require regulatory registration for impurity toxicity identification of the acaracinib maleate tablet formulated with the drug substance prepared in method B.
Example 13: preparation of acaracitinib maleate tablets
Fig. 31 provides a schematic of a process for preparing the acaracinib maleate tablet T21 of example 4. Specifically, acaracitinib maleate, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose were added to a suitable diffusion mixer and mixed together. The intra-granular fraction of sodium stearyl fumarate was added to the powder and mixed prior to roller compaction. The lubricating mixture is rolled to form a ribbon. The ribbon is then ground into granules by passing the ribbon through a suitable grinder. The granulate is mixed with the extragranular fraction 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 coating suspension was prepared and applied to the tablet cores using conventional film coating processes.
Example 14: study of relative bioavailability
Phase 1, open label, single dose, sequential randomized study of acarabtinib maleate tablets was performed in healthy human subjects to evaluate relative bioavailability, proton pump inhibitor (rabeprazole) effect, food effect and particle size effect. The study was divided into two study sections. Study section 1 was conducted to test the relative bioavailability of the acaracinib maleate tablets and the acaracinib free base capsules, and as a preliminary study, information was provided for the design of study section 2. Study section 1 also aimed to test the effect of proton pump inhibitors ("PPIs") and the effect of food on acaracinib maleate tablet exposure. After reviewing the safety and pharmacokinetic data of section 1, the study will proceed to section 2. Study section 2 is directed to testing the effect of drug substance particle size change on acaracinib maleate tablet exposure and the relative bioavailability of acaracinib maleate tablets compared to solution. The results of the study will provide information on the pharmacokinetic and pharmacodynamic profiles of the acarabtinib maleate tablets to be evaluated.
A.Design of research
Study object of part 1
The main purpose is as follows:
assessing the relative bioavailability of the acaracinib maleate tablets compared to the acaracinib free base capsules in the fasted state.
For the secondary purposes:
evaluation of ACP-5862 pharmacokinetic profiles of acaracinib maleate tablets compared to acaracinib free base capsules in the fasted state.
Assessing the effect of the proton pump inhibitor rabeprazole on the pharmacokinetic profile of acamprintine and its metabolites (ACP-5862) obtained after administration of the acamprintine maleate tablet.
Assessing the effect of food on the pharmacokinetics of acaracinib and its metabolites (ACP-5862) obtained after administration of acaracinib maleate tablets.
Assessing the safety and tolerability of a single dose of acarabtinib maleate tablets in healthy subjects.
Measuring the pharmacodynamic parameter BTK receptor occupancy of the acaracinib maleate tablets and the acaracinib free base capsules in the isolated PBMCs.
Exploratory purposes:
assessment of exposure differences by helicobacter pylori breath test status (presence versus absence).
SmartPill pH information was collected and used as input to the PBPK model to calculate individual in vivo dissolution.
Study object of part 2
The main purpose is as follows:
assessing the effect of drug substance particle size on bioavailability of acaracinib maleate tablets.
The secondary purpose is as follows:
evaluate the effect of drug substance particle size on ACP-5862 pharmacokinetic profile of acarabtinib maleate tablets.
Comparing the pharmacokinetics of the acaracinib maleate tablets compared to the acaracinib oral solution in healthy subjects.
Evaluating the safety and tolerability of single dose acarabtinib maleate tablets with different drug substance particle size distributions in healthy subjects.
Evaluating the safety, tolerability, taste and odor of a single dose of the oral acarabtinib solution in healthy subjects.
Study design part 1:
part 1 of the study is a randomized crossover study of one open label, three treatment sessions, four treatments, single-center relative bioavailability, PPI effect and food effect on new acartitinib maleate tablets in healthy subjects (male or female with no fertility potential).
Study section 1 included:
a screening period of up to 28 days;
three treatment periods during which the subject will remain until at least 48 hours post-dose from the evening meal of the night prior to dosing (day-1) and be discharged on day 3 morning; and
visit within 7 to 10 days.
There will be a minimum washout period of 7 days between each acaracinib administration. Under fasting or fed conditions, each subject will receive three of the following four treatments over three treatment periods: subjects will be randomized to receive treatment a or B in treatment periods 1 and 2, followed by treatment C or D in treatment period 3. The 100mg acaracinib maleate tablet (variant 1) has the composition of tablet T21 (see example 4, table 7) with D of the drug substance (v,0.9) The particle size is not more than 218 mu m.
Treatment A:100mg acaracinib free base capsules in fasted state (> 10 h).
Treatment B:100mg acaracitinib maleate tablets (variant 1), fasted state (> 10 h).
Treatment C:100mg acaracitinib maleate tablets (variant 1), fed state.
Treatment D: rabeprazole 20mg x 1 (fasted) was taken 2 hours before administration of 100mg of the acarabinib maleate tablet (variant 1) on days-3, -2 and-1 and 2 hours after prior administration of rabeprazole 20mg BID (with meal).
* For each subject, smartPill would be administered with 120mL of still water, followed immediately by a single oral dose of acamprintine maleate tablets (treatment B, C or D) or acamprintine free base capsules (treatment a) administered with 120mL of still water, followed by PK sampling over 24 hours.
* Subjects will start consuming a high fat (according to FDA) meal 30 minutes before SmartPill/100mg acarabtinib maleate tablet administration. The subject will be asked to finish the meal within 25 minutes; however, smartPill/IMP should be administered 30 minutes after the start of a meal.
Study design section 2:
part 2 of the study will be an open label, 4 treatment cycles, 4 treatments, randomized crossover study of single-center relative bioavailability to determine the effect of particle size on single dose acarabtinib maleate tablet PK in healthy subjects (male or female with no fertility potential).
Study section 2 included:
a screening period of up to 28 days;
four treatment periods during which the subject will remain until at least 48 hours post-dose before the evening meal of the night prior to dosing (day-1) and be discharged in the morning on day 3; and
visit within 7 to 10 days.
There will be a minimum washout period of at least 3 days between each administration of acaracinib.
Each subject will receive the following treatments:
treatment A:100mg acarabtinib maleate tablets (variant 1), fasted state
Treatment B:100mg acaracinib maleate tablets (variant 2), fasted state
Treatment C:100mg acaracinib maleate tablets (variant 3), fasted state
Treatment D:100mg acarabtinib solution in fasted state
100mg acaracinib maleate tablets (variant 1) contained drug substance with medium particle size, while 100mg acaracinib maleate tablets (variant 2) contained drug substance with smaller particle size, and 100mg acaracinib maleate tablets (variant 3) contained drug substance with larger particle size. Specifically, a 100mg acaracinib maleate tablet has the composition of tablet T21 (see example 4,table 7), wherein variant 1 comprises D having no more than 218 μm (v,0.9) Drug substance of particle size, variant 2 comprising D having a particle size of not more than 160 μm (v,0.9) A drug substance of particle size, and variant 3 comprises D having a particle size of no greater than 319 μm (v,0.9) The drug substance in the particle size of the drug substance,
expected duration of the study
In part 1, each subject will participate in the study for approximately 7 to 8 weeks. In part 2, each subject will participate in the study for approximately 6 to 7 weeks.
Target study population
In part 1 of the study, a total of 28 healthy male and female subjects between the ages of 18 and 55 years (inclusive) will be included to ensure that there are at least 24 subjects evaluable. In part 2 of the study, a total of 24 healthy male and female subjects between 18 and 55 years of age (inclusive) will be included to ensure that there are 20 evaluable subjects at the end of the last treatment period.
End of result
Pharmacokinetic end point:
continuous venous blood samples were obtained for determination of acaracinib and metabolite (ACP-5862) concentrations in plasma. Where possible, pharmacokinetic parameters will be evaluated for plasma concentrations of acarabtinib and the metabolite ACP-5862.
Parts 1 and 2:
major PK parameters: acarabtinib C max ，AUC Finally, the ，AUC inf
Secondary PK parameters: ACP-5862C max ，AUC Finally, the ，AUC inf (ii) a Acaracitinib and ACP-5862: AUC 0-12 、AUC Finally, the step of 、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 Finally, the 、AUC inf ACP-5862 (metabolite)To acaracinib (parent) ratio (M/P).
Additional PK parameters may be determined where appropriate.
Safety and tolerability endpoints:
the security and resistance variables will include:
adverse event/severe adverse event.
Laboratory evaluation (hematology, clinical chemistry, coagulation and urinalysis).
Physical examination.
Electrocardiogram (12-lead ECG).
Vital signs (systolic and diastolic pressure, pulse rate, respiratory rate, body temperature).
Taste and smell assessments (section 2 only).
Exploratory endpoint (part 1):
acarabtinib and ACP-5862: repeated measures analysis of covariance (ANCOVA) will be used to analyze PK parameters (AUC) Finally, the 、AUC inf And C max ) And evaluating the difference in exposure by gastric pH and gastric emptying rate using appropriate statistical procedures
The overall GI tract temperature, pH and pressure profiles; gastric pH (part 1 only) immediately after administration of the acaracitinib product (first measurable Point)
Breath test status of H.pylori
Part 1 statistical methods
To assess the relative bioavailability of the acamprovinib maleate tablets compared to the acamprovinib free base capsules in the fasted state, the main PK parameters of acamprovinib and its metabolite ACP-5862 were compared between treatments B (acamprovinib) and a (acamprovinib free base capsules). The analysis will be performed as follows: analysis of Linear Mixed Effect Using a model of variance, using C max 、AUC inf And AUC Finally, the The natural logarithm of (a) as a response variable, the sequence, cycle, treatment as a fixed effect, and volunteers nested in the sequence as a random effect.Conversion from logarithmic scale back and in the case of CI (95% on 2-side), AUC is estimated and presented inf 、AUC Finally, the And C max Geometric mean of (a). In addition, in the case of CI (2-side 90%), the ratio of the geometric mean is estimated and presented.
To evaluate the effect of the proton pump inhibitor rabeprazole on the PK profile of acamprintib and its metabolite (ACP-5862) obtained after administration of the acamprintib maleate tablets, the main PK parameters of acamprintib and its metabolite ACP-5862 between treatment D (rabeprazole) compared to B (acamprintib) were compared from the same analysis of variance (ANOVA) model.
To assess the effect of food on the PK of acamprovinib and its metabolite (ACP-5862) obtained after administration of acamprovinib maleate tablets, the main PK parameters of acamprovinib and its metabolite ACP-5862 between treatment C (fed) versus B (fasted) will be compared from the same ANOVA model.
Part 2 statistical methods
To assess the effect of drug substance particle size on acamprintine maleate tablet bioavailability, the primary PK parameters of acamprintine and its metabolite ACP-5862 will be compared between treatment B (less than target) compared to a (target), C (greater than target) compared to a (target) and C (greater than target) compared to B (less than target), and will be analyzed as follows: linear mixture Effect analysis Using an ANOVA model, using C max 、AUC inf And AUC Finally, the The natural logarithm of (a) as a response variable, sequence, cycle, treatment as a fixed effect, and volunteers nested in the sequence as a random effect. Conversion from logarithmic scale back and in the case of CI (95% on 2-side), AUC is estimated and presented inf 、AUC Finally, the And C max Geometric mean of (a). In addition, in the case of CI (2-side 90%), the ratio of the geometric mean is estimated and presented.
To compare the PK of acaracinib maleate tablets versus acaracinib oral solutions, the main PK parameters of acaracinib and its metabolite ACP-5862 would be compared between treatment D (solution) versus a (target) from the same ANOVA model.
Part 1 and part 2 statistical methods
Furthermore, the 90-percentile CI for the median tmax difference will be calculated and presented using the same comparison from ANOVA. The median difference and 90% confidence interval for each comparison and analyte are tabulated.
It is expected that the results will demonstrate that co-administration of PPI or other acid reducing agent with acaracinib maleate tablets does not affect exposure of acaracinib and ACP-5862.
B.Results of the study
Pharmacokinetics
The results of study section 1 show that acaracinib maleate tablets (variant 1) and acaracinib capsules have similar bioavailability.
Mean pharmacokinetic exposure of acaracinib and metabolite ACP-5862 after oral administration of acaracinib maleate tablets (variant 1) in fasted state compared to acaracinib capsules (C) max And AUC). Acaracitinib C max And relative bioavailability of AUC of about 91% and 98%, ACP-5862C max And AUC is about 100% and 103% to 104%, respectively.
Co-administration of PPI (rabeprazole) with the acarbatinib maleate tablet (variant 1) had no significant effect on the pharmacokinetic exposure of acarbatinib and the metabolite ACP-5862. Acarabtinib C max Slightly lower (about 24% difference in geometric mean), slightly higher AUC (about 14% to 17% difference in geometric mean). C of ACP-5862 max About 30% lower, with comparable AUC in the presence compared to the absence of PPI.
For Yu A Carragtinib maleate tablets (variant 1), diet Calabrtinib and ACP-5862C max Reduced by about 54% and 36%, respectively, and had no effect on overall AUC.
C of acaracinib and ACP-5862 because there was no difference in BTK occupancy between treatments max Up to about 81% inter-subject variability (geometric CV%), C observed max The difference is unlikely to have a clinically meaningful effect.
Tables 12-16 below set forth a summary of plasma pharmacokinetic parameters for part 1 of this study.
TABLE 12
Part 1: summary of plasma pharmacokinetic parameters for acarabtinib
A:100mg acarabetinib capsule in fasted state
B:100mg acaracinib maleate tablets (variant 1), fasted state
C:100mg acaracinib maleate tablet (variant 1), fed state
D: 20mg rabeprazole QD (fasted) was taken 2 hours before the administration of 100mg of the acarabinib maleate tablet (variant 1) on days-3, -2 and-1 and 2 hours after the prior administration of 20mg rabeprazole BID (with meal).
BID = twice daily; CV = coefficient of variation; max = maximum; min = minimum; n = number of subjects in PK analysis set; QD = once per day; SD = standard deviation.
Watch 13
Part 1: summary of plasma pharmacokinetic parameters for metabolite ACP-5862
A:100mg acarabetinib capsule in fasted state
B:100mg acaracinib maleate tablets (variant 1), fasted state
C:100mg acaracinib maleate tablet (variant 1), fed state
D: 20mg rabeprazole QD (fasted) was taken 2 hours before the administration of 100mg of the acarabinib maleate tablet (variant 1) on days-3, -2 and-1 and 2 hours after the prior administration of 20mg rabeprazole BID (with meal).
BID = twice daily; CV = coefficient of variation; max = maximum; min = minimum; n = number of subjects in PK analysis set; QD = once per day; SD = standard deviation.
/>
TABLE 16
Part 1: statistical comparison of pharmacokinetic parameters for food effect assessment
B:100mg acaracinib maleate tablets (variant 1), fasted state
C:100mg acaracinib maleate tablet (variant 1), fed state.
Only subjects with effective PK parameters from both treatments were included for statistical analysis.
Results of linear mixed effect ANOVA based on logarithmically transformed PK parameters, sequence, treatment as fixed effect; and subjects nested in the sequence as random effects. The geometric mean ratio and the corresponding 90%CI are back-converted and expressed in percentages. The geometric LSM and the corresponding 95% CI are also back-transformed. ANOVA = analysis of variance; CI = confidence interval; LSM = least squares means; n = number of subjects in PK analysis set; n = number of subjects included in the statistical comparative analysis; PK = pharmacokinetics.
The results of study 2 indicate that the acamprovinib maleate particle size had no significant effect on the pharmacokinetics of acamprovinib and ACP-5862 within the assessed particle size range. After administration, variants 1, 2 and 3 all resulted in comparable pharmacokinetic exposures.
Mean pharmacokinetic exposure of acaracinib and metabolite ACP-5862 after oral administration of acaracinib maleate tablets (variants 1, 2 and 3) of different particle size (C) max And AUC) are similar. 90% of the geometric mean ratio CI is close to or entirely within 80% to 125% margin.
The acaracinib solution has a higher C than the acaracinib maleate tablet (variant 1) max And comparable AUC. Acaracitinib C max And AUC, about 122% and 102%, ACP-5862C max And AUC was approximately 124% and 106% to 107%, respectively.
Tables 17-21 set forth a summary of plasma pharmacokinetic parameters in part 2 of the study.
TABLE 17
Section 2: summary of plasma pharmacokinetic parameters for acarabtinib
f Data for 23 subjects are included in the summary; the overall concentration of one subject was not quantifiable and therefore PK parameters could not be calculated.
A:100mg acaracinib maleate tablets (variant 1), fasted state
B:100mg acarabtinib maleate tablet (variant 2), fasted state
C:100mg acaracinib maleate tablets (variant 3), fasted state
D:100mg acaracinib solution in fasted state.
CV = coefficient of variation; max = maximum; min = minimum; n = number of subjects in the pharmacokinetic analysis set; PK = pharmacokinetics; SD = standard deviation.
Watch 18
Section 2: summary of plasma pharmacokinetic parameters for metabolite ACP-5862
g Data for 23 subjects are included in the summary; the overall concentration of one subject was not quantifiable and therefore PK parameters could not be calculated.
A:100mg acaracinib maleate tablets (variant 1), fasted state
B:100mg acaracinib maleate tablets (variant 2), fasted state
C:100mg acarabtinib maleate tablets (variant 3), fasted state;
d:100mg acaracinib solution in fasted state.
CV = coefficient of variation; max = maximum; min = minimum; n = number of subjects in the pharmacokinetic analysis set; PK = pharmacokinetics; SD = standard deviation.
/>
TABLE 21
Part 2: statistical comparison of pharmacokinetic parameters for assessment of relative bioavailability
A:100mg acaracinib maleate tablets (variant 1), fasted state
D:100mg acaracinib solution in fasted state.
Results of linear mixed effect ANOVA based on logarithmically transformed PK parameters, sequence, treatment as fixed effect; and subjects nested in the sequence as random effects. The geometric mean ratio and the corresponding 90% CI are back-transformed and expressed in percentage. Geometric LSM and the corresponding 95% CI are also back-transformed. ANOVA = analysis of variance; CI = confidence interval; LSM = least squares means; n = number of subjects in PK analysis set; n = number of subjects included in the statistical comparative analysis; PK = pharmacokinetics.
Pharmacodynamics of medicine
Part 1 of the study investigated BTK receptor occupancy when acaracinib is administered as a capsule or tablet. The results show that BTK occupancy was similar in all post-dose time points (4, 12 and 24 hours) after tablet and capsule administration. Furthermore, the BTK occupancy of the tablet formulation is not affected by food or PPI application.
Exploratory property
It was found that gastric pH did not affect the acaracinib maleate exposure of a 100mg acaracinib maleate film coated tablet, and thus the in vivo dissolution of the tablet was not sensitive to gastric pH.
Safety feature
Overall, no new safety issues were found for the 100mg acarabtinib maleate film-coated tablets, and the new formulations were well tolerated.
Example 15: bioequivalence assessment
An open label, randomized, two-way crossover bioequivalence study was performed in healthy subjects to evaluate the bioequivalence of acaracinib maleate tablets (test formulation) and acaracinib free base capsules (reference formulation). The study was intended to demonstrate, according to regulatory requirements, that the acaracinib maleate tablets and the acaracinib free base capsules are bioequivalent.
Study name:
phase I, open label, randomized, 2 treatments, 2 cycles, crossover studies were performed in healthy subjects to assess bioequivalence of the acarabtinib tablets and acarabtinib capsules.
The basic principle of research is as follows:
acaracitinib is a Biopharmaceutical Classification System (BCS) class II drug (high permeability, low solubility) that exhibits two basic dissociation constants in the physiological pH range. The solubility of acaracitinib decreases with increasing pH. Below pH 4, the drug is highly soluble. However, in patients taking antacids (i.e. pH above 4), the solubility of the drug in the stomach/intestine is not sufficient to ensure complete dissolution and absorption of the drug. Previous observations from phase I studies (study ACE-HV-112) showed that when 100mg of acaracinib capsules were administered after once daily (qd) 40mg omeprazole (a Proton Pump Inhibitor (PPI)) dosing, the AUC was reduced by 43%, C, compared to when the drug was dosed under normal acidic pH conditions max The reduction is 72%.
At a dose of 100mg equivalent free fraction, the Acaracinib Maleate Tablet (AMT) showed in vitro pH dependent release compared to the acaracinib capsule (i.e. calsequence). The results of the relative bioavailability study (see example 14) indicate that systemic exposure of acartinib and its active metabolite ACP-5862 after AMT administration is similar in the presence or absence of PPIs and comparable to those observed with 100mg acartinib capsules. This bioequivalence study was aimed at confirming that 100mg AMT abolished the influence of PPIs on the Pharmacokinetics (PK) of acartitinib in humans.
Number of subjects planned
Approximately 64 subjects (approximately 32 per treatment sequence) will be randomized to ensure that at least 52 subjects (26 per sequence) can be evaluated at the end of treatment period 2.
Purpose of study
The main purpose is as follows:
the bioequivalence of AMT and acarabtinib capsules administered in the fasted state was demonstrated.
The secondary purpose is as follows:
comparative pharmacokinetic profiles of ACP-5862 (an active metabolite of acarabtinib) after AMT and acarabtinib capsules administration.
Compare the safety and tolerability of single dose AMT and alcalatinib capsules.
Exploratory purposes:
measure the Pharmacodynamics (PD) of acarabtinib.
Design of research
This study will be a multicenter, phase I, open label, randomized, 2 sequence, 2 treatments, 2 cycles, crossover, bioequivalence study with single dose oral administration of alcazabrib in healthy subjects at approximately three study centers in the united states. The study was aimed to demonstrate bioequivalence of AMT in fasted state (treatment a) compared to the commercial alcapratinib capsule (treatment B).
The study will include:
visit 1: a screening period of up to 28 days prior to the first dose.
Visit 2: two treatment cycles:
subjects will enter the study center on day-2 of treatment cycle 1 to qualify prior to first dose. The qualifying criteria will be confirmed again on day-1 of each treatment cycle.
o on days 1 of treatment cycles 1 and 2, subjects will be administered the indicated treatment (a or B) randomly, followed by at least five days of washout between treatment cycles 1 and 2.
After completion of the scheduled study assessments, subjects will be discharged from the study center on the 3 rd morning of treatment cycle 2.
Visit 3: follow-up visit 7 to 10 days after the last IMP administration/visit was terminated early.
At the follow-up visit/early termination visit, the telemedicine visit may replace the on-site visit or a portion thereof as necessary (laboratory testing, ECG, and tympanic temperature checks will not be performed when the telemedicine visit is performed). The term telemedicine visit refers to a virtual or video visit. During social crises, natural disasters, or public health crises (e.g., COVID-19 pandemics), on-site visits may be replaced by remote medical visits if permitted by local/regional guidelines. Telemedicine contact with the subject will allow collection of Adverse Events (AEs) and concomitant medications according to the study requirements to be reported and recorded.
Subjects will receive either treatment sequence 1 (AB) or treatment sequence 2 (BA) at random. AMT has the composition of tablet T21 (see example 4, table 7) in which D of the drug substance (v,0.9) The particle size is not more than 218 mu m.
Treatment A: AMT,100mg, fasted state.
Treatment B: acaracitinib capsule, 100mg, fasted state.
Subjects will receive a fixed single dose of acarabtinib twice under fasting conditions.
Expected duration of the study
Each subject will participate in the study for approximately six weeks.
Target study population
Healthy adult male and female subjects 18-55 years old inclusive, with BMI 18.5-30kg/m2 inclusive, and who are non-smoking; women must be of infertile potential.
Test and reference formulations
End of result
Safety and tolerability endpoint：
Adverse events.
Laboratory evaluation (hematology, coagulation, clinical chemistry and urinalysis).
Physical examination.
Electrocardiogram (ECG).
Vital signs (systolic pressure [ BP ], diastolic pressure, pulse, respiratory rate, tympanic membrane, temperature).
Pharmacokinetic end point:
the main PK parameters:
acaracinib-AUC inf 、AUC Finally, the 、C max
Secondary PK parameters:
acarabtinib-t max 、t 1/2 λz、MRT、λz、CL/F、Vz/F
·ACP-5862-AUC inf 、AUC Finally, the 、C max 、t max 、t 1/2 λz、MRT、λz、M:P[AUC]、M:P[C max ]
Statistical method
All statistical analysis and production of tables, graphs and lists will be usedVersion 9.4 or later.
Analyzing the data set:
the safety analysis set will include all subjects who received at least one dose in treatment cycle 1 and for which post-dose safety data was available. The PK analysis set will consist of all subjects in the safety analysis set who have at least one quantifiable post-dose concentration of acarabinib and no significant protocol bias or adverse events thought to affect PK data analysis. The random set will consist of all subjects randomized into the study.
Presentation and analysis of safety and tolerability data:
all security data (both planned and unplanned) will be displayed in the data list. Continuous variables will be summarized by treatment using descriptive statistics (number of subjects [ n ], mean, standard deviation [ SD ], minimum, median, maximum). The categorical variables will be summarized by treatment in frequency tables (frequency and scale). The analysis of the security variables will be based on a set of security analyses.
Adverse events will be summarized by System Organ Classification (SOC) and preferred terminology (using the current version of the supervised active Medical Dictionary (MedDRA) vocabulary). Data tables and lists of vital signs, clinical laboratory tests and ECGs will be provided. Any new or aggravated findings of the clinically relevant abnormal medical physical examination will be reported as an adverse event as compared to the baseline assessment. Clinical laboratory data will be reported in units provided by clinical laboratories and in units international to the system.
Presentation of pharmacokinetic data:
a list of PK blood sample collection times and derived sampling time offsets will be provided. For each analyte, plasma concentrations and PK parameters will be summarized by treatment. Diagnostic PK parameters will be summarized and listed. The table will be based on the PK analysis set. Data for subjects excluded from the PK analysis set will be included in the data list, but not in descriptive or inferred statistics. For each analyte, the individual plasma concentrations will be plotted against actual time on a linear and semi-logarithmic scale, with all treatments superimposed on the same plot and on separate plots for each subject. Pooled individual plasma concentrations will be plotted on a linear and semi-log scale compared to actual time, with a separate plot for each treatment and analyte. Geometric mean plasma concentrations will be plotted in a linear scale (—/+ geometric SD) and a semilogarithmic scale (geometric SD not presented) compared to nominal sampling time, with all treatments superimposed on the same plot and a separate plot for each analyte. All figures will be based on the PK analysis set, except for the individual figures divided by subject, which will be based on the safety analysis set.
Statistical analysis of pharmacokinetic data:
treatment will be evaluated according to the PK analysis set a: AMT (test) and treatment B: bioequivalence between acaracinib capsules (reference). The analysis will be performed as follows: linear Mixed Effect analysis Using an ANOVA model, using acarabtinib C max 、AUC Finally, the And AUC inf The natural logarithm of (a) as a response variable, the sequence, cycle, treatment as a fixed effect, and the subjects nested in the sequence as a random effect. Conversion from logarithmic scale back and in case of Confidence Interval (CI) (2-side 95%), C is estimated and presented max 、AUC Finally, the step of And AUC inf Geometric mean of (a). In addition, in the case of CI (2-side 90%), the ratio of the geometric mean is estimated and presented. In addition, C of acarabtinib and ACP-5862 will be estimated and presented, respectively max 、AUC inf And AUC Finally, the Inter% CV and intra% CV.
Bioequivalence criteria:
if C between test and reference max And AUC Finally, the Or AUC inf 90% of the log-transformed geometric mean ratio of (a) ci is completely contained within 80.00% and 125.00%, then it can be concluded that the two treatments are bioequivalent. Statistical analysis to establish bioequivalence will be performed by combining PK data from all study centers.
Presentation and analysis of pharmacodynamic data:
exploratory PD parameters (BTK receptor occupancy) results will be listed and summarized as appropriate according to the pharmacokinetic analysis set.
Determination of sample amount:
c according to acarabtinib max And AUC inf The bioequivalence of (C) is in the range of 80.00% to 125.00%, cmax in-subject CV 29.8%, AUC inf With an intra-subject CV of 15.1% (study ACE-HV-115) and an "test/reference" average ratio of 0.95, 52 evaluable subjects were required to achieve 90% efficacy.
Overall, a total of 64 subjects will each provide at least 95% efficacy to derive information about C max And AUC inf A bioequivalence conclusion of each of them.
VIII.Examples
Example 1: a solid pharmaceutical dosage form comprising from about 75mg to about 125mg (free base equivalent) acarabtinib maleate and at least one pharmaceutically acceptable excipient for oral administration to a human, wherein the dosage form satisfies the following conditions: (i) At least about 75% of the acaracitinib maleate dissolves in about 30 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium, and 50RPM paddle rotation; and (ii) at least about 75% of the acaracinib maleate is dissolved in about 60 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate pH6.8 dissolution medium, and paddle rotation speed of 75 RPM.
Example 2: the dosage form of example 1, wherein the dosage form satisfies the following conditions: (i) At least about 75% of the acaracitinib maleate dissolves in about 20 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium, and 50RPM paddle rotation; and (ii) at least about 75% of the acaracinib maleate is dissolved in about 45 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate pH6.8 dissolution medium, and paddle rotation speed of 75 RPM.
Example 3: the dosage form of example 1, wherein the dosage form satisfies the following conditions: (i) At least about 80% of the acaracitinib maleate dissolves in about 20 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium, and 50RPM paddle rotation; and (ii) at least about 80% of the acaracinib maleate is dissolved in about 30 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate pH6.8 dissolution medium, and paddle rotation speed of 75 RPM.
Example 4: the dosage form of example 1, wherein the dosage form satisfies the following conditions: (i) At least about 80% of the acaracitinib maleate dissolves in about 15 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium, and 50RPM paddle rotation; and (ii) at least about 80% of the acaracinib maleate is dissolved in about 20 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate pH6.8 dissolution medium, and paddle rotation speed of 75 RPM.
Example 5: the dosage form of any one of embodiments 1 to 4, wherein the acaracinib maleate is acaracinib maleate monohydrate.
Example 6: the dosage form of embodiment 5, wherein the acamprovinib maleate monohydrate is crystalline form a.
Example 7: the dosage form of any one of embodiments 1 to 6, wherein at least one pharmaceutically acceptable excipient is selected from at least one diluent, at least one disintegrant, and at least one lubricant.
Example 8: the dosage form of any one of embodiments 1 to 7, wherein the dissolution rate of acarabinib maleate in a 5mM phosphate pH6.8 dissolution medium does not decrease by more than 20% from its initial dissolution rate after six months storage at 40 ℃ and 75% relative humidity in suitable packaging.
Example 9: the dosage form of any one of embodiments 1 to 7, wherein the dissolution rate of acarabetiib maleate in a 5mM phosphate pH6.8 dissolution medium does not decrease by more than 10% from its initial dissolution rate after six months storage at 40 ℃ and 75% relative humidity in suitable packaging.
Example 10: the dosage form of any one of embodiments 1 to 7, wherein the dissolution rate of acarabinib maleate in a 5mM phosphate pH6.8 dissolution medium does not decrease by more than 5% from its initial dissolution rate after six months storage at 40 ℃ and 75% relative humidity in suitable packaging.
Example 11: the dosage form of any one of embodiments 1 to 7, wherein the dissolution rate of acarabinib maleate in a 5mM phosphate pH6.8 dissolution medium does not decrease by more than 2% from its initial dissolution rate after six months storage at 40 ℃ and 75% relative humidity in suitable packaging.
Example 12: the dosage form of any one of embodiments 1 to 11, wherein the acaracinib maleate present in the dosage form does not exceed about 5% (w/w) degradation after storage in suitable packaging at 40 ℃ and 75% relative humidity for six months.
Example 13: the dosage form of any one of embodiments 1 to 11, wherein no more than about 2% (w/w) degradation of the acaracinib maleate present in the dosage form occurs after six months storage in suitable packaging at 40 ℃ and 75% relative humidity.
Example 14: the dosage form of any one of embodiments 1 to 11, wherein no more than about 1% (w/w) degradation of the acaracinib maleate present in the dosage form occurs after six months storage in suitable packaging at 40 ℃ and 75% relative humidity.
Example 15: the dosage form of any one of embodiments 1 to 11, wherein no more than about 0.5% (w/w) degradation of the acaracinib maleate present in the dosage form occurs after six months storage in suitable packaging at 40 ℃ and 75% relative humidity.
Example 16: the dosage form of any one of embodiments 1 to 15, wherein the dosage form is bioequivalent to 100mg when orally administered to a fasting human subject that is not administered a gastric antacidA capsule wherein the relative mean Cmax, AUC (0-t), and AUC when said dosage form is administeredConfidence interval of (0- ∞) relative to 100 mg->The dosage form is bioequivalent when the capsule is within 80% to 125%.
Example 17: the dosage form of any one of embodiments 1 to 15, wherein the dosage form, when administered twice daily to a population of fasting human subjects, satisfies one or more of the following pharmacokinetic conditions for acarabetiib: (i) A mean Cmax value in the population of human subjects of about 400ng/mL to about 900ng/mL; (ii) (ii) a mean AUC (0-24) value in the population of human subjects of about 350 ng-hr/mL to about 1900 ng-hr/mL; and/or (iii) the mean AUC (0- ∞) value in the population of human subjects is about 350 ng-hr/mL to about 1900 ng-hr/mL.
Example 18: the dosage form of embodiment 17, wherein the dosage form is co-administered with a gastric acid reducing agent to the population of human subjects.
Example 19: the dosage form of any one of embodiments 1 to 18, wherein the dosage form provides a median steady-state bruton's tyrosine kinase occupancy of at least about 90% in peripheral blood mononuclear cells when administered twice daily to a human subject.
Example 20: the dosage form of any one of embodiments 1 to 18, wherein the dosage form provides a median steady-state bruton's tyrosine kinase occupancy of at least about 95% in peripheral blood mononuclear cells when administered twice daily to a human subject.
Example 21: the dosage form of embodiment 19 or 20, wherein the dosage form is co-administered with a gastric acid reducing agent to the population of human subjects.
Example 22: the dosage form of any one of embodiments 1 to 21, wherein the acaracinib maleate is present in an amount from about 15% to about 55% (free base equivalent) by weight of the dosage form.
Example 23: the dosage form of any one of embodiments 1 to 21, wherein the acaracinib maleate is present in an amount from about 20% to about 50% (free base equivalent) by weight of the dosage form.
Example 24: the dosage form of any one of embodiments 1 to 21, wherein the acaracinib maleate is present in an amount from about 25% to about 50% (free base equivalent) by weight of the dosage form.
Example 25: the dosage form of any one of embodiments 1 to 21, wherein the acamprovinib maleate is present in an amount from about 25% to about 40% (free base equivalents) by weight of the dosage form.
Example 26: the dosage form of any one of embodiments 1 to 25, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent.
Example 27: the dosage form of embodiment 26, wherein the at least one diluent is present in an amount from about 10% to about 70% by weight of the dosage form.
Example 28: the dosage form of embodiment 26, wherein the at least one diluent is present in an amount from about 20% to about 70% by weight of the dosage form.
Example 29: the dosage form of embodiment 26, wherein the at least one diluent is present in an amount from about 30% to about 70% by weight of the dosage form.
Example 30: the dosage form of embodiment 26, wherein the at least one diluent is present in an amount from about 40% to about 70% by weight of the dosage form.
Example 31: the dosage form of any one of embodiments 26 to 30, wherein the at least one diluent does not affect the stability of the primary amine moiety of acaracinib.
Example 32: the dosage form of any one of embodiments 26 to 30, wherein the at least one diluent does not comprise lactose.
Example 33: the dosage form of any one of embodiments 26 to 32, wherein the at least one diluent does not comprise a maleic acid scavenger.
Example 34: the dosage form of any one of embodiments 26 to 33, wherein the at least one diluent does not comprise anhydrous dibasic calcium phosphate.
Example 35: the dosage form of any one of embodiments 26 to 34, wherein the at least one diluent comprises a plastic diluent and a brittle diluent.
Example 36: the dosage form of embodiment 35, wherein the w/w ratio of plastic diluent to friable diluent is about 0 to about 60.
Example 37: the dosage form of embodiment 35 or 36, wherein: (i) The at least one diluent comprises 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 friable diluent is present in an amount of about 0% to about 50% by weight of the dosage form.
Example 38: the dosage form of any one of embodiments 26 to 34, wherein the at least one diluent comprises mannitol.
Example 39: the dosage form of any one of embodiments 26 to 34, wherein the at least one diluent comprises microcrystalline cellulose.
Example 40: the dosage form of any one of embodiments 26 to 34, wherein the at least one diluent comprises mannitol and microcrystalline cellulose.
Example 41: the dosage form of embodiment 40, wherein the w/w ratio of mannitol to microcrystalline cellulose is from about 0 to about 100 to about 60.
Example 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.
Example 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.
Example 44: the dosage form of embodiment 40, wherein: (i) The mannitol is present in an amount of about 0% to about 70% by weight of the dosage form; (ii) The microcrystalline cellulose is present in an amount of about 0% to about 50% by weight of the dosage form; and (iii) mannitol and microcrystalline cellulose in a total amount of about 10% to about 70% by weight of the dosage form.
Example 45: the dosage form of any of embodiments 26 to 44, wherein the weight ratio of acamprovinib maleate (free base equivalent) to the at least one diluent is about 1:3 to about 2:1.
Example 46: the dosage form of any one of embodiments 26 to 44, wherein the weight ratio of acamprovine maleate (free base equivalent) to the at least one diluent is about 1:1 to about 1:2.
Example 47: the dosage form of any one of embodiments 1 to 46, wherein the at least one pharmaceutically acceptable excipient comprises at least one disintegrant.
Example 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.
Example 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.
Example 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.
Example 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.
Example 52: the dosage form of any one of embodiments 47 to 51, wherein the at least one disintegrant does not comprise an ionic disintegrant.
Example 53: the dosage form of any one of embodiments 47 to 51, wherein the at least one disintegrant does not comprise sodium starch glycolate.
Example 54: the dosage form of any one of embodiments 47 to 53, wherein the at least one disintegrant does not comprise croscarmellose sodium.
Example 56: the dosage form of any one of embodiments 47 to 54, wherein the at least one disintegrant comprises a non-ionic disintegrant.
Example 57: the dosage form of any one of embodiments 47 to 56, wherein the at least one disintegrant comprises hydroxypropyl cellulose.
Example 58: the dosage form of any one of embodiments 47 to 56, wherein the at least one disintegrant comprises low substituted hydroxypropyl cellulose.
Example 59: the dosage form of any one of embodiments 47 to 59, wherein the weight ratio of acaracinib maleate (free base equivalent) to the at least one disintegrant is about 2:1 to about 15.
Example 60: the dosage form of any one of embodiments 47 to 59, wherein the weight ratio of acaracinib maleate (free base equivalent) to the at least one disintegrant is about 4:1 to about 10.
Example 61: the dosage form of any one of embodiments 1 to 60, wherein the at least one pharmaceutically acceptable excipient comprises at least one lubricant.
Example 62: the dosage form of embodiment 61, wherein the at least one lubricant is present in an amount from about 0.25% to about 4% by weight of the dosage form.
Example 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.
Example 64: the dosage form of any one of embodiment 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.
Example 65: the dosage form of any one of embodiment 61, wherein the at least one lubricant is present in an amount of about 2% to about 3% by weight of the dosage form.
Example 66: the dosage form of any one of embodiments 61 to 65, wherein the at least one lubricant does not comprise magnesium stearate.
Example 67: the dosage form of any one of embodiments 51 to 66, wherein the at least one lubricant does not comprise glyceryl dibehenate.
Example 68: the dosage form of any one of embodiments 61 to 67, wherein the at least one lubricant comprises sodium stearyl fumarate.
Example 69: the dosage form of any one of embodiments 61 to 68, wherein the weight ratio of acaracinib maleate (free base equivalent) to the at least one lubricant is from about 20 to about 1.
Example 70: the dosage form of any one of embodiments 61 to 68, wherein the weight ratio of acaracinib maleate (free base equivalent) to the at least one lubricant is from about 18 to about 1.
Example 71: the dosage form of any one 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.
Example 72: the dosage form of embodiment 7, wherein the dosage form comprises: (i) Acaracitinib maleate in an amount from about 15% to about 55% (free base equivalents) by weight of the dosage form; (ii) At least one diluent in an amount from about 10% to about 70% by weight of the dosage form; (iii) At least one disintegrant in an amount from about 0.5% to about 15% by weight of the dosage form; and (iv) at least one lubricant in an amount from about 0.25% to about 4% by weight of the dosage form; and wherein the sum of the amounts equals 100% of the total weight of the dosage form.
Example 73: the dosage form of embodiment 7, wherein the dosage form comprises: (i) Acaracitinib maleate in an amount from about 20% to about 50% (free base equivalent) by weight of the dosage form; (ii) At least one diluent in an amount from about 20% to about 70% by weight of the dosage form; (iii) At least one disintegrant in an amount from about 1% to about 10% by weight of the dosage form; and (iv) at least one lubricant in an amount from about 1% to about 4% by weight of the dosage form; and wherein the sum of the amounts equals 100% of the total weight of the dosage form.
Example 74: the dosage form of embodiment 7, wherein the dosage form comprises: (i) Acaracitinib maleate in an amount from about 25% to about 50% (free base equivalent) by weight of the dosage form; (ii) At least one diluent in an amount from about 30% to about 70% by weight of the dosage form; (iii) At least one disintegrant in an amount from about 2% to about 8% by weight of the dosage form; and (iv) at least one lubricant in an amount from about 1.5% to about 3.5% by weight of the dosage form; and wherein the sum of the amounts equals 100% of the total weight of the dosage form.
Example 75: the dosage form of embodiment 7, wherein the dosage form comprises: (i) Acaracitinib maleate in an amount from about 25% to about 40% (free base equivalent) by weight of the dosage form; (ii) At least one diluent in an amount from about 40% to about 70% by weight of the dosage form; (iii) At least one disintegrant in an amount from about 3% to about 7% by weight of the dosage form; and (iv) at least one lubricant in an amount from about 2% to about 3% by weight of the dosage form; and wherein the sum of the amounts equals 100% of the total weight of the dosage form.
Example 76: the dosage form of embodiment 7, wherein the dosage form comprises: (i) Acaracitinib maleate in an amount from 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 from 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 from about 1% to about 4% by weight of the dosage form; and wherein the sum of the amounts equals 100% of the total weight of the dosage form.
Example 77: the dosage form of any one of embodiments 1 to 76, wherein the acaracinib maleate has a D (v, 0.9) value less than about 500 microns.
Example 78: the dosage form of any one of embodiments 1 to 76, wherein the acaracinib maleate has a D (v, 0.9) value less than about 450 microns.
Example 79: the dosage form of any one of embodiments 1 to 76, wherein the acaracinib maleate has a D (v, 0.9) value less than about 400 microns.
Example 80: the dosage form of any one of embodiments 1 to 76, wherein the acaracinib maleate has a D (v, 0.9) value less than about 350 microns.
Example 81: the dosage form of any one of embodiments 1 to 76, wherein the acaracinib maleate has a D (v, 0.9) value less than about 300 microns.
Example 82: the dosage form of any one of embodiments 1 to 76, wherein the acaracinib maleate has a D (v, 0.9) value of about 20 to about 500 microns.
Example 83: the dosage form of any one of embodiments 1 to 76, wherein the acamprovinib maleate has a D (v, 0.9) value from about 50 microns to about 450 microns.
Example 84: the dosage form of any one of embodiments 1 to 76, wherein the acaracinib maleate has a D (v, 0.9) value of about 75 to about 400 microns.
Example 85: the dosage form of any one of embodiments 1 to 76, wherein the acaracinib maleate has a D (v, 0.9) value of about 75 to about 350 microns.
Example 86: the dosage form of any one of embodiments 1 to 76, wherein the acaracinib maleate has a D (v, 0.9) value of about 100 to about 300 microns.
Example 87: the dosage form of any one of embodiments 1 to 86, wherein the dosage form is a capsule.
Example 88: the capsule of embodiment 87, wherein the capsule is prepared by a process comprising roller compaction.
Example 89: the dosage form of any one of embodiments 1 to 86, wherein the dosage form is a tablet.
Example 90: the dosage form of any one of embodiments 1 to 86, wherein the dosage form is a film coated tablet.
Example 91: the tablet of embodiment 89 or 90, wherein the tablet is prepared by a process comprising direct compression.
Example 92: the tablet of embodiment 89 or 90, wherein the tablet is prepared by a process comprising roller compaction.
Example 93: the tablet of any one of embodiments 89 to 92, wherein the tablet has a tensile strength of about 1.5MPa to about 5.0 MPa.
Example 94: the tablet of any one of embodiments 89 to 92, wherein the tablet has a tensile strength of about 2.0 to about 4.0 MPa.
Example 95: the tablet of any one of embodiments 89 to 94, wherein the tensile strength of the tablet does not decrease more than 10% from its initial tensile strength after six months of storage of the tablet in blister packs at 40 ℃ and 75% relative humidity.
Example 96: the tablet of any one of embodiments 89 to 94, wherein the tensile strength of the tablet does not decrease more than 8% from its initial tensile strength after six months of storage of the tablet in blister packs at 40 ℃ and 75% relative humidity.
Example 97: the tablet of any one of embodiments 89 to 94, wherein the tensile strength of the tablet does not decrease more than 5% from its initial tensile strength after six months of storage of the tablet in blister packs at 40 ℃ and 75% relative humidity.
Example 98: a method of treating a BTK-mediated disorder in a subject suffering from or susceptible to the disorder, the method comprising administering to the subject once or twice daily a solid pharmaceutical dosage form as described in any one of embodiments 1 to 97.
***********
This written description uses examples to disclose the invention and enable any person skilled in the art to practice the invention, including making and using any salts, materials, or compositions of the disclosure, and performing any methods or processes of the disclosure. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. 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 include equivalent elements with insubstantial differences from the literal languages of the claims. While preferred embodiments of the present invention have been illustrated and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the present 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 this disclosure are not intended to be limiting.
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 portion of any reference) is relevant prior art (or prior art). Applicants reserve the right to challenge the accuracy and pertinency of the cited references.
Claims (22)
1. A solid pharmaceutical dosage form comprising from about 75mg to about 125mg (free base equivalent) acarabtinib maleate and at least one pharmaceutically acceptable excipient for oral administration to a human, wherein the dosage form satisfies the following conditions:
at least about 75% of the acarabtinib maleate dissolves in about 30 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium and paddle speed of 50 RPM; and
at least about 75% of the acarabtinib maleate dissolved in about 60 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate ph6.8 dissolution medium and paddle rotation speed of 75 RPM.
2. The dosage form of claim 1, wherein the dosage form satisfies the following conditions:
at least about 80% of the acaracitinib maleate dissolves in about 15 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 0.1N hydrochloric acid dissolution medium, and 50RPM paddle rotation; and
at least about 80% of the acaracitinib maleate dissolves in about 20 minutes as determined in an in vitro dissolution test using USP dissolution apparatus 2 (paddle apparatus), 900mL dissolution volume, 5mM phosphate ph6.8 dissolution medium, and paddle rotation speed of 75 RPM.
3. The dosage form of claim 1 or 2, wherein the acaracinib maleate is crystalline acaracinib maleate monohydrate form a.
4. The dosage form of any one of claims 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.
5. The dosage form of any one of claims 1 to 4, wherein the dissolution rate of acarabinib maleate in a 5mM phosphate pH6.8 dissolution medium does not decrease by more than 20% from its initial dissolution rate after six months storage at 40 ℃ and 75% relative humidity in suitable packaging.
6. The dosage form of any one of claims 1 to 5, wherein no more than about 5% (w/w) degradation of the acaracinib maleate is present in the dosage form after six months storage in suitable packaging at 40 ℃ and 75% relative humidity.
7. The dosage form of any one of claims 1 to 6, wherein the dosage form is bioequivalent to 100mg when orally administered to a fasting human subject that is not administered a gastric antacidCapsules wherein the relative average C of the dosage forms max 、AUC (0-t) And AUC (0-∞) Is compared with a confidence interval of 100mg>The dosage form is bioequivalent when the capsule is within 80% to 125%.
8. The dosage form of any one of claims 1 to 7, wherein the acaracinib maleate is present in an amount of about 100mg (free base equivalent).
9. The dosage form of any one of claims 1 to 8, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent.
10. The dosage form of claim 9, wherein the at least one diluent does not affect the stability of the primary amine moiety of acaracinib.
11. The dosage form of claim 9 or 10, wherein the at least one diluent comprises a plastic diluent and a brittle diluent.
12. The dosage form of any one of claims 9 to 11, wherein the weight ratio of acamprovine maleate (free base equivalent) to the at least one diluent is about 1:3 to about 2:1.
13. The dosage form of any one of claims 1 to 12, wherein the at least one pharmaceutically acceptable excipient comprises at least one disintegrant.
14. The dosage form of claim 13, wherein the at least one disintegrant does not comprise an ionic disintegrant.
15. The dosage form of claim 13 or 14, wherein the weight ratio of acamprovinib maleate (free base equivalent) to the at least one disintegrant is from about 2:1 to about 15.
16. The dosage form of claim 4, wherein the dosage form comprises:
acaracitinib maleate in an amount from about 15% to about 55% (free base equivalents) by weight of the dosage form;
at least one diluent in an amount from about 10% to about 70% by weight of the dosage form;
at least one disintegrant in an amount from about 0.5% to about 15% by weight of the dosage form; and
at least one lubricant in an amount from about 0.25% to about 4% by weight of the dosage form; and is
Wherein the sum of the amounts equals 100% of the total weight of the dosage form.
17. The dosage form of claim 4, wherein the dosage form comprises:
acamprovinib maleate in an amount from about 30% to about 35% (free base equivalents) 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 from 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 from about 1% to about 4% by weight of the dosage form; and is provided with
Wherein the sum of the amounts equals 100% of the total weight of the dosage form.
18. The dosage form of any one of claims 1 to 17, wherein the acaracinib maleate has a D of about 20 microns to about 500 microns (v,0.9) The value is obtained.
19. The dosage form of any one of claims 1 to 18, wherein the dosage form is a tablet.
20. The tablet of claim 19, wherein the tablet has a tensile strength of about 1.5MPa to about 5.0 MPa.
21. The tablet of claim 20, wherein the tensile strength of the tablet does not decrease more than 10% from its initial tensile strength after six months of storage of the tablet in blister packs at 40 ℃ and 75% relative humidity.
22. A method of treating a BTK-mediated disorder in a subject suffering from or susceptible to the disorder, the method comprising administering to the subject once or twice daily a solid pharmaceutical dosage form of any one of claims 1 to 21.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63/041197 | 2020-06-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK40083774A true HK40083774A (en) | 2023-06-30 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2538925B1 (en) | Apixaban formulations | |
| HK1243947A1 (en) | Apixaban formulations | |
| HK1243945A1 (en) | Apixaban formulations | |
| US12036224B2 (en) | Formulations, methods, kits, and dosage forms for treating atopic dermatitis and for improved stability of an active pharmaceutical ingredient | |
| AU2024204906A1 (en) | Acalabrutinib maleate dosage forms | |
| WO2004054574A1 (en) | Solid drug for oral use | |
| EP2514422B1 (en) | Elution stabilized teneligliptin preparation | |
| HK40083774A (en) | Acalabrutinib maleate dosage forms | |
| EP3641735B1 (en) | Pharmaceutical tablet composition comprising bilastine form 3 and a water-soluble filler | |
| EA047001B1 (en) | DOSAGE FORMS OF ACALABRUTINIB MALEATE | |
| EA049364B1 (en) | DOSAGE FORMS OF ACALABRUTINIB MALEATE | |
| BR112022025611B1 (en) | Acalabrutinib maleate tablets, their uses, and kits. | |
| HK40029900A (en) | Apixaban formulations | |
| HK40031930A (en) | Apixaban formulations | |
| HK1180248B (en) | Apixaban formulations | |
| HK1243946B (en) | Apixaban formulations | |
| HK1224216B (en) | Apixaban formulations |