Pharmaceutical compositions comprising (2S)-n-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

Abstract

To provide pharmaceutical compositions comprising (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide or a salt thereof, and methods for treating obstructive airway diseases.SOLUTION: A pharmaceutical composition comprises from about 1.0 to about 30 wt.% of (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide; from about 55 to about 75 wt.% of a pharmaceutical diluent; from about 15% to about 25% of a compression aid; from about 3.0% to about 5.0 wt.% of a pharmaceutical disintegrant; from about 0.00 to about 1.0 wt.% of a pharmaceutical glidant; and from about 2 to about 6 wt.% of a pharmaceutical lubricant.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. Provisional Patent Application No. 62 / 636,944, filed March 1, 2018, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] The present disclosure relates to pharmaceutical compositions containing the compound (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (or "Compound A"), or a pharmaceutically acceptable salt thereof. Compound A has the following structural formula: [ka] It has.

[0003] Compound A and pharmaceutically acceptable salts thereof are disclosed as inhibitors of dipeptidyl peptidase (DPP1; EC3.4.14.1) in U.S. Patent No. 6,277,623 (incorporated herein by reference in its entirety for all purposes). U.S. Patent No. 6,277,623 also describes the use of Compound A in the treatment and / or prevention of clinical conditions, including respiratory diseases (e.g., asthma, bronchiectasis, and chronic obstructive pulmonary disease (COPD)), therapeutic applications of Compound A, pharmaceutical compositions containing Compound A, and methods for preparing Compound A. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent Application Publication No. 2015 / 0210655 Summary of the Invention

[0005] In one embodiment, the compound of formula (I): [ka] [In the formula, R 1 teeth, [ka] and; R 2 are hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C 1-3 is alkyl; R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or R 6 may be substituted by 1, 2 or 3 F and / or OH, OC 1-3 Alkyl, N(C 1-3 alkyl), optionally substituted by cyclopropyl or tetrahydropyran; C 1-3 is alkyl; R 7 is hydrogen, F, Cl or CH3; X is O, S or CF2; Y is O or S; Q is CH or N. or a pharmaceutically acceptable salt thereof.

[0006] The composition further comprises about 55 to about 75 wt% of a pharmaceutical diluent, about 15% to about 25% of a compression aid, about 3.0% to about 5.0 wt% of a pharmaceutical disintegrant, about 0.00 to about 1.0 wt% of a pharmaceutical glidant; and about 2 to about 6 wt% of a pharmaceutical lubricant; wherein the weights of the components add up to 100.

[0007] In one embodiment of the compositions provided herein, the pharmaceutical composition comprises glycerol behenate as a pharmaceutical lubricant.

[0008] In one embodiment of the compositions provided herein, the pharmaceutical composition comprises microcrystalline cellulose as a diluent.

[0009] In another embodiment, the pharmaceutical compositions provided herein comprise dibasic calcium phosphate dihydrate as a compression aid.

[0010] One embodiment of the compositions provided herein includes a composition comprising sodium starch glycolate as a pharmaceutical disintegrant.

[0011] Yet another embodiment is directed to a pharmaceutical composition comprising silicon dioxide as a glidant.

[0012] In one embodiment, the pharmaceutical composition comprises about 1.0 to about 30 wt% (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (Compound A); about 55 to about 75 wt% pharmaceutical diluent, about 15% to about 25% compression aid, about 3.0% to about 5.0 wt% pharmaceutical disintegrant, about 0.00 to about 1.0 wt% pharmaceutical glidant; and about 2 to about 6 wt% pharmaceutical lubricant; wherein the weights of the components add up to 100. In a further embodiment, the diluent is microcrystalline cellulose, the compression aid is dibasic calcium phosphate dihydrate, the disintegrant is sodium starch glycolate, the glidant is silicon dioxide, and the lubricant is glycerol behenate.

[0013] Another aspect of the present invention is directed to a method for treating an obstructive airway disease in a patient in need thereof. The method comprises administering to the patient in need thereof one of the compositions provided herein. In one embodiment, the composition comprises Compound A as the compound represented by formula (I). In a further embodiment, the obstructive airway disease is bronchiectasis or cystic fibrosis. In a further embodiment, the obstructive airway disease is bronchiectasis.

[0014] Another aspect of the present invention is directed to a method for treating antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis in a patient in need of such treatment. The method comprises administering to a patient in need thereof one of the compositions provided herein. In one embodiment, the composition comprises Compound A as the compound of Formula (I). In one embodiment, the ANCA-associated vasculitis is granulomatosis with polyangiitis (GPA). In another embodiment, the ANCA-associated vasculitis is microscopic polyangiitis (MPA). In one embodiment, the patient has active ANCA-associated vasculitis (e.g., active GPA or MPA). In another embodiment, the patient is in remission of ANCA-associated vasculitis (e.g., in remission of GPA or MPA). [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 is a flow diagram of an embodiment of a process for making one of the compositions of the present invention. [Figure 2] Figure 2 shows an overlay of chromatograms of the three tested compositions with different lubricants compared to the API (Compound A) and a standard. The chromatograms are slightly offset for clarity. [Figure 3] FIG. 3 shows the scaled and centered coefficient values ​​obtained from the multiple linear regression (MLR) models for the five degradation products of Compound A as a function of excipient, temperature, or relative humidity (RH). [Figure 4]Figure 4 shows the scaled and centered coefficient values ​​from the MLR analysis of the shelf-life prediction data for the various excipients tested. [Figure 5] Figure 5 shows steps in the fabrication process captured using SEM images. [Figure 6] Figure 6 shows scanning electron microscope (SEM) images of each step in the manufacturing process. [Figure 7] FIG. 7 is a graph of the particle size distribution of the final blends of formulations N1 to N11. [Figure 8] Figure 8 shows the coefficient plot of the decomposition after one month for 40 / 75. [Figure 9] FIG. 9 is a graph of tablet tensile strength (MPa) from the lubrication test as a function of compression pressure (MPa) for various formulations. [Figure 10] Figure 10 is the dissolution profile of the 5 mg formulation from the first lubrication trial initially and after 1 month storage at 40 / 75. [Figure 11] FIG. 11 is the dissolution profile of the 65 mg formulation from the first lubrication test under pristine conditions. [Figure 12] FIG. 12 is a graph of excipient level (percentage of core weight) as a function of API dose. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description of the Invention As used herein, "C 1-3 " means a carbon group having 1, 2 or 3 carbon atoms.

[0017] The term "alkyl," unless otherwise specified, includes both straight and branched chain alkyl groups, which may be substituted or unsubstituted. "Alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, and pentyl.

[0018] The term "pharmaceutically acceptable" is used, unless otherwise specified, to characterize a moiety (e.g., a salt, a dosage form, or an excipient) as being appropriate for use according to sound medical judgment. Generally, a pharmaceutically acceptable moiety has one or more advantages that outweigh any adverse effects that the moiety may have. Adverse effects may include, for example, excessive toxicity, irritation, allergic reaction, and other problems and complications.

[0019] By "effective amount" or "therapeutically effective amount" is meant the amount of disease-modifying compound A, or a pharmaceutically acceptable salt thereof, used in the present invention sufficient to bring about the desired therapeutic response.

[0020] Those skilled in the art will understand that certain pharmaceutical excipients can be used in anhydrous form or one or more hydrated forms.For example, lactose can be used in anhydrous form or monohydrate form.Similarly, dibasic calcium phosphate can be used in anhydrous form or dihydrate form.In this disclosure, if the hydration level of a pharmaceutical excipient is not explicitly mentioned, it should be understood that any and all conventional hydration levels are included in this term.Therefore, "lactose" (without further qualification) includes lactose monohydrate, lactose in anhydrous form, and mixtures thereof.

[0021] Similarly, one skilled in the art will understand that calcium phosphate can be used in dibasic or tribasic form. In this disclosure, "calcium phosphate" (without further qualification) includes the dibasic form, the tribasic form, and mixtures thereof.

[0022] In this disclosure, "wt%" refers to "weight percent" and has the ordinary meaning customary in the art. Thus, "wt%" refers to the proportion of component X in composition Y, calculated in each case based on the weight of component X and composition Y (as opposed to other physical parameters such as volume or number of moles present). For example, if 2 g of component X is present in 20 g of composition Y, then component X constitutes 10 wt% of composition Y.

[0023] As described herein, the ingredients of pharmaceutical compositions are described in terms of "parts," where "all parts are by weight." Such language should be understood to simply define the relative proportions of the ingredients, where the proportions are defined in terms of relative weight (as opposed to other physical parameters, such as volume or number of moles present). As an example, if 1 g of component X and 4 g of component Z are present in a mixture where the sum of parts of component X and parts of component Z is defined to equal 100, then in this example, 20 parts of component X and 80 parts of component Z are present in the mixture.

[0024] composition In one aspect, the present invention provides one or more compounds of formula (I): [ka] [In the formula, R 1 teeth, [ka] and; R 2 are hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C 1-3 is alkyl; R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or R 6 may be substituted by 1, 2 or 3 F and / or OH, OC 1-3 Alkyl, N(C 1-3 alkyl), optionally substituted by cyclopropyl or tetrahydropyran; C 1-3 is alkyl; R 7is hydrogen, F, Cl or CH3; X is O, S or CF2; Y is O or S; Q is CH or N. or a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, R 1 teeth, [ka] and;R 2 are hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C 1-3 alkyl; R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine ring, a pyrrolidine ring, or a piperidine ring.

[0026] In a further embodiment, R 1 teeth, [ka] and;R 2 is hydrogen, F, Cl or C 1-3 alkyl; R 3 is hydrogen, F, Cl, CN or SO2C 1-3 It is alkyl.

[0027] In still further embodiments, R 1 teeth, [ka] and;R 2 is hydrogen, F or C 1-3 alkyl; R 3 is hydrogen, F or CN.

[0028] In another embodiment, R 1 teeth, [ka] X is O, S, or CF2; Y is O or S; Q is CH or N; R 6 is C 1-3 alkyl, wherein the C 1-3 The alkyl may be substituted by 1, 2 or 3 F and / or by OH, OC 1-3 Alkyl, N(C 1-3 alkyl), cyclopropyl or tetrahydropyran; R 7 is hydrogen, F, Cl or CH3.

[0029] In still further embodiments, R 1 teeth, [ka] X is O, S, or CF2; Y is O or S; R 6 may be substituted by 1, 2 or 3 F, and OH, OC 1-3 Alkyl, N(C 1-3 alkyl), optionally substituted by cyclopropyl or tetrahydropyran; C 1-3 alkyl; R 7 is hydrogen, F, Cl or CH3.

[0030] In still further embodiments, R 1 teeth, [ka] X is O, S or CF2; R 6 is C 1-3 alkyl, wherein the C 1-3 Alkyl may be substituted by 1, 2 or 3 F; R 7is hydrogen, F, Cl or CH3.

[0031] In still further embodiments, R 1 teeth, [ka] and X is O and R 6 is C 1-3 alkyl, wherein the C 1-3 Alkyl may be substituted by 1, 2 or 3 F; R 7 is hydrogen.

[0032] In one embodiment, R 2 are hydrogen, F, Cl, Br, OSO2C 1-3 Alkyl or C 1-3 It is alkyl.

[0033] In a further embodiment, R 2 is hydrogen, F, Cl or C 1-3 It is alkyl.

[0034] In still further embodiments, R 2 is hydrogen, F or C 1-3 It is alkyl.

[0035] In one embodiment, R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2 or SO2NR 4 R 5 where R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine ring, a pyrrolidine ring, or a piperidine ring.

[0036] In a further embodiment, R 3 is hydrogen, F, Cl, CN or SO2C 1-3 alkyl.

[0037] In still further embodiments, R 3is selected from hydrogen, F or CN.

[0038] In one embodiment, R 6 is C 1-3 alkyl, wherein the C 1-3 The alkyl may be substituted by 1, 2 or 3 F and may be substituted by OH, OC 1-3 Alkyl, N(C 1-3 It may be substituted by one substituent selected from alkyl), cyclopropyl, or tetrahydropyran.

[0039] In a further embodiment, R 6 is C 1-3 alkyl, wherein the C 1-3 The alkyl may be substituted by 1, 2 or 3 F. In yet a further embodiment, R 6 is methyl or ethyl. In yet a further embodiment, R 6 is methyl.

[0040] In one embodiment, R 7 is hydrogen, F, Cl, or CH3. In a further embodiment, R 7 is hydrogen.

[0041] In one embodiment, the compound of formula (I) is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide: [ka] or a pharmaceutically acceptable salt thereof.

[0042] In one embodiment, the compound of formula (I) is: (2S)—N-[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, 4'-[(2S)-2-cyano-2-{[(2S)-1,4-oxazepan-2-ylcarbonyl]amino}ethyl]biphenyl-3-yl methanesulfonate, (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-1,2-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4'-(trifluoromethyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-(3′,4′-difluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(6-cyanopyridin-3-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3-ethyl-7-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-7-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-(4-{3-[2-(dimethylamino)ethyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}phenyl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[2-oxo-3-(propan-2-yl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(5-cyanothiophen-2-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-2-(4′-carbamoyl-3′-fluorobiphenyl-4-yl)-1-cyanoethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-2-[4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[3-(2,2-difluoroethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-{4-[2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-1-cyano-2-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-{(1S)-2-[4'-(azetidin-1-ylsulfonyl)biphenyl-4-yl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, (2S)—N-[(1S)-1-cyano-2-(4′-fluorobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide, (2S)-N-{(1S)-2-[4-(1,3-benzothiazol-5-yl)phenyl]-1-cyanoethyl}-1,4-oxazepane-2-carboxamide, or (2S)-N-[(1S)-1-cyano-2-(4'-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide or a pharmaceutically acceptable salt of one or more of the above.

[0043] Methods for synthesizing compounds of Formula (I) are disclosed in PCT Application Publication No. 2015 / 110826, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0044] In one embodiment, the compound of Formula (I) is "Compound A." Compound A, as used herein, is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide. Compound A, also known as INS1007 or AZD7986, has the following structural formula: [ka] It has.

[0045] Methods for synthesizing Compound A are disclosed in U.S. Patent Application Publication No. 2015 / 0210655, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0046] Compound A can be used in free base form, or as a pharmaceutically acceptable salt, or as a mixture thereof. In certain embodiments, Compound A is in free base form. "Free base form" is understood to refer to the case where Compound A is not in the form of a salt.

[0047] In some embodiments of the present disclosure, Compound A is in the form of a pharmaceutically acceptable salt.

[0048] The pharmaceutically acceptable salt of Compound A can be formed with inorganic or organic acid.The pharmaceutically acceptable salt can be formed with inorganic acid selected from, for example, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.The pharmaceutically acceptable salt can also be formed with organic acid selected from, for example, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.

[0049] In some embodiments, Compound A is polymorphic Form A of the free base form of Compound A. Polymorphic Form A of the free base form of Compound A is disclosed in U.S. Patent Application Publication No. 2015 / 0210655, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0050] In some embodiments, Compound A is the free base form of Compound A and is characterized by an X-ray powder diffraction pattern having a peak at about 12.2±0.2 (°2θ) measured using CuKα radiation.

[0051] In some embodiments, Compound A is the free base form of Compound A and is characterized by an X-ray powder diffraction pattern having a peak at about 20.6±0.2 (°2θ) measured using CuKα radiation.

[0052] In some embodiments, Compound A is the free base form of Compound A and is characterized by an X-ray powder diffraction pattern having peaks at about 12.2±0.2° and about 20.6±0.2° (°2θ) measured using CuKα radiation.

[0053] In some embodiments, Compound A is the free base form of Compound A and is characterized by an X-ray powder diffraction pattern having peaks at about 12.2±0.2, about 14.3±0.2, about 16.2±0.2, about 19.1±0.2, and about 20.6±0.2 (°2θ) as measured using CuKα radiation.

[0054] Unless otherwise specified herein, the API weight percentages provided herein are relative to the respective free base forms.

[0055] In some embodiments, the compositions described herein include a compound of Formula (I), e.g., Compound A, in an amount of about 1.0 to about 30 wt %; about 1.0 to about 25 wt %; about 1.0 to about 20 wt %; about 1.0 to about 15 wt %; about 1.0 to about 10 wt %; about 1.0 to about 5 wt %, or about 1.0 to about 3 wt %.

[0056] In some embodiments, the compositions described herein include a compound of Formula (I), e.g., Compound A, in an amount of about 1.5 to about 30 wt %; about 1.5 to about 25 wt %; about 1.5 to about 20 wt %; about 1.5 to about 15 wt %; about 1.5 to about 10 wt %; or about 1.5 to about 5 wt %.

[0057] In some embodiments, the compositions described herein include a compound of Formula (I), e.g., Compound A, in an amount of about 3 to about 30 wt%; about 3 to about 25 wt%; about 3 to about 20 wt%; about 3 to about 15 wt%; about 3 to about 10 wt%; or about 3 to about 5 wt%.

[0058] In one embodiment, the compositions described herein include a compound of Formula (I), e.g., Compound A, in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%.

[0059] In one embodiment, the compositions described herein include a compound of Formula (I), e.g., Compound A, in an amount of 10 mg to 50 mg, e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In a further embodiment, the compositions described herein include a compound of Formula (I) in an amount of 10 mg, 25 mg, or 40 mg. In yet a further embodiment, the compound is Compound A, or a pharmaceutically acceptable salt thereof.

[0060] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: about 1 to about 30 wt % of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; about 55 to about 75 wt% pharmaceutical diluent; Compaction aid: about 15 to about 25 wt%; about 3 to about 5 wt% of a pharmaceutical disintegrant; about 0.00 to about 1 wt % of a pharmaceutical glidant; and Pharmaceutical lubricant: about 2 to about 6 wt% (wherein said ingredients total 100 wt%).

[0061] In certain embodiments, the compound of formula (I) is Compound A in its free base form.

[0062] The pharmaceutical compositions of the present disclosure may be in a solid dosage form suitable for oral administration to humans.

[0063] In certain embodiments, the pharmaceutical composition of the present disclosure is a pharmaceutical tablet. Pharmaceutical tablets can be prepared using methods known to those skilled in the art, including, for example, the dry blend / direct compression process described herein (see Examples section).

[0064] In some embodiments, the pharmaceutical tablet comprises a tablet core comprising a pharmaceutical composition as defined herein, the tablet core comprising a coating. In some embodiments, the coating is a film coating. Suitable film coatings are discussed herein.

[0065] The pharmaceutical compositions of the present disclosure, in one embodiment, comprise one or more pharmaceutical diluents. The term "diluent" is used interchangeably with "filler."

[0066] Suitable pharmaceutical diluents are known to those skilled in the art of pharmaceutical formulation science.Suitable pharmaceutical diluents include, for example, microcrystalline cellulose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose and xylitol.

[0067] In one embodiment, the one or more pharmaceutical diluents is microcrystalline cellulose. Microcrystalline cellulose is a binder / diluent in oral tablet and capsule formulations and can be used in dry granulation, wet granulation, and microcompression processes. Typical concentrations when used as a tablet diluent are 20-90%.

[0068] In some embodiments, the pharmaceutical compositions of the present disclosure comprise two or more pharmaceutical diluents.

[0069] In one embodiment, the compositions described herein comprise one or more pharmaceutical diluents in an amount of about 45 to about 85 wt%, about 45 to about 80 wt%, about 45 to about 75 wt%, about 45 to about 70 wt%, about 45 to about 65 wt%, about 45 to about 60 wt%, or about 45 to about 55 wt%. In a further embodiment, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In yet a further embodiment, the API in the formulation is Compound A or a pharmaceutically acceptable salt thereof.

[0070] In another embodiment, the compositions described herein comprise one or more pharmaceutical diluents in an amount of about 45 to about 85 wt%, about 50 to about 85 wt%, about 50 to about 75 wt%, about 55 to about 85 wt%, about 55 to about 70 wt%, about 60 to about 85 wt%, about 65 to about 85 wt%, about 70 to about 85 wt%, or about 75 to about 85 wt%. In a further embodiment, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In yet a further embodiment, the API in the formulation is Compound A or a pharmaceutically acceptable salt thereof.

[0071] In one embodiment, the compositions described herein comprise one or more pharmaceutical diluents in an amount of about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, or about 85 wt%.

[0072] In certain embodiments, one or more pharmaceutical diluents are microcrystalline cellulose.In further such embodiments, one or more pharmaceutical diluents comprise calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose and xylitol.

[0073] As used herein, the term "disintegrant" is intended to be interpreted in the context of pharmaceutical formulation science. Thus, the disintegrant may be, for example, alginic acid, calcium alginate, calcium carboxymethylcellulose, chitosan, croscarmellose sodium, crospovidone, glycine, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose, sodium starch glycolate, starch, or a combination thereof.

[0074] In one embodiment, one or more disintegrants is sodium starch glycolate. In one embodiment, the concentration (wt%) used in the formulation is 2% to 8%. In a further embodiment, the concentration is about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, or about 4.5 wt%. The physical properties of sodium starch glycolate, and therefore its effectiveness as a disintegrant, are affected by the degree of cross-linking, the degree of carboxymethylation, and purity.

[0075] In one embodiment, the one or more pharmaceutical disintegrants include croscarmellose sodium.

[0076] In certain embodiments, the compositions described herein comprise one or more pharmaceutical disintegrants in an amount of about 1 to about 15 wt%, about 2 to about 14 wt%, about 2 to about 13 wt%, about 2 to about 12 wt%, about 2 to about 11 wt%, about 2 to about 10 wt%, about 2 to about 9 wt%, about 2 to about 8 wt%, about 2 to about 7 wt%, about 2 to about 6 wt%, or about 2 to about 5 wt%. In further embodiments, the one or more pharmaceutical disintegrants are sodium starch glycolate. In further embodiments, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In yet further embodiments, the API in the formulation is Compound A or a pharmaceutically acceptable salt thereof.

[0077] The term "glidant" is intended to be interpreted in the context of pharmaceutical formulation science. Thus, glidants can be, for example, silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate, and talc.

[0078] Thus, in particular embodiments, the one or more pharmaceutical glidants (d) comprise one or more pharmaceutical glidants selected from silicon dioxide, colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate, and talc.

[0079] In one embodiment, the glidant is silicon dioxide. Its small particle size and large specific surface area provide desirable flow properties that are utilized to improve the flow properties of dry powders in many processes, such as tableting and capsule filling. Typical silicon dioxide concentrations for use herein range from about 0.05 to about 1.0 wt%. Porous silica gel particles can also be used as a glidant, which may be advantageous for some formulations, with typical concentrations being 0.25 to 1%.

[0080] In one embodiment, the compositions described herein comprise one or more pharmaceutical glidants in an amount of about 0.00 to about 2 wt%; about 0.00 to about 1.75 wt%; about 0.00 to about 1.50 wt%; about 0.00 to about 1.25 wt%; about 0.00 to about 1.00 wt%; about 0.00 to about 0.75 wt%; about 0.00 to about 0.50 wt%; about 0.00 to about 0.25 wt%; or about 0.00 to about 0.20 wt%. In a further embodiment, the one or more pharmaceutical glidants comprise silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants are sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In yet a further embodiment, the API in the composition is Compound A or a pharmaceutically acceptable salt thereof.

[0081] In one embodiment, the compositions described herein comprise one or more pharmaceutical glidants in an amount of about 0.05 to about 2 wt%; about 0.05 to about 1.75 wt%; about 0.05 to about 1.50 wt%; about 0.05 to about 1.25 wt%; about 0.05 to about 1.00 wt%; about 0.05 to about 0.75 wt%; about 0.05 to about 0.50 wt%; about 0.05 to about 0.25 wt%; or about 0.05 to about 0.20 wt%. In a further embodiment, the one or more pharmaceutical glidants comprise silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants are sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In yet a further embodiment, the API in the composition is Compound A or a pharmaceutically acceptable salt thereof.

[0082] In one embodiment, the compositions described herein comprise one or more pharmaceutical glidants in an amount of about 0.00 to about 2 wt%; 0.05 to about 2 wt%; 0.10 to about 2 wt%; 0.2 to about 2 wt%; 0.3 to about 2 wt%; or about 0.40 to about 2 wt%. In a further embodiment, the one or more pharmaceutical glidants comprise silicon dioxide. In a further embodiment, the one or more pharmaceutical disintegrants are sodium starch glycolate. In a further embodiment, the one or more pharmaceutical diluents comprise microcrystalline cellulose. In yet a further embodiment, the API in the composition is Compound A or a pharmaceutically acceptable salt thereof.

[0083] The term "lubricant," as used herein, is intended to be interpreted in the context of pharmaceutical formulation science. Thus, the lubricant can be, for example, calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenic esters of glycerin (e.g., a mixture of glyceryl bibehenate, tribehenin, and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin, and zinc stearate.

[0084] Thus, in certain embodiments, the one or more pharmaceutical lubricants (e) comprise one or more pharmaceutical lubricants selected from calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenic acid esters of glycerin (e.g., a mixture of glyceryl bibehenate, tribehenin, and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, tribehenin, and zinc stearate.

[0085] In other specific embodiments, the one or more pharmaceutical lubricants (e) comprise one or more pharmaceutical lubricants selected from calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenic acid esters of glycerin (e.g., a mixture of glyceryl bibehenate, tribehenin, and glyceryl behenate), leucine, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, stearic acid, talc, tribehenin, and zinc stearate.

[0086] Pharmaceutical compositions containing Compound A exhibit specific degradants when sodium stearyl fumarate is the lubricant. The data in Table 8 (below) show that the impurity with a relative retention time of 1.03 (i.e., Compound A-fumaric acid salt Michael adduct) is present only when sodium stearyl fumarate is the lubricant. In some embodiments, the pharmaceutical composition includes one or more pharmaceutical lubricants (e), and the lubricant is not sodium stearyl fumarate.

[0087] In one embodiment, the formulations provided herein contain glycerol behenate as a lubricant.

[0088] According to one embodiment of the present disclosure, the one or more pharmaceutical lubricants (e) include glyceryl behenate, magnesium stearate, stearic acid, or a combination thereof.

[0089] In one embodiment, the lubricant is glyceryl behenate, magnesium stearate, or a combination thereof.

[0090] In one embodiment, the one or more pharmaceutical lubricants include sodium stearyl fumarate and / or one or more behenic acid esters of glycerin.

[0091] According to one embodiment, the pharmaceutical composition comprises one or more pharmaceutical lubricants in an amount of about 1 wt% to about 10 wt%, 1 wt% to about 9 wt%, 1 wt% to about 8 wt%, 1 wt% to about 7 wt%, 1 wt% to about 6 wt%, 1 wt% to about 5 wt%, about 2 wt% to about 10 wt%, about 2.5 wt% to about 10 wt%, about 2 wt% to about 8 wt%, about 2 wt% to about 7 wt%, about 2 wt% to about 6 wt%, about 2 wt% to about 5 wt%, about 2 wt% to about 4.5 wt%, or about 2.5 wt% to about 4.5 wt%. In a further embodiment, the one or more pharmaceutical lubricants in the composition are glycerol behenate. In a further embodiment, the one or more pharmaceutical glidants in the composition include silicon dioxide. In a further embodiment, one or more pharmaceutical disintegrants in the composition are sodium starch glycolate. In a further embodiment, one or more pharmaceutical diluents comprise microcrystalline cellulose. In yet a further embodiment, the API in the composition is Compound A or a pharmaceutically acceptable salt thereof.

[0092] In another embodiment, the one or more pharmaceutical lubricants (e) consist of sodium stearyl fumarate and / or one or more behenic acid esters of glycerin or mixtures thereof.

[0093] In another embodiment, the one or more pharmaceutical lubricants (e) consist of sodium stearyl fumarate, glyceryl dibehenate, glyceryl behenate, tribehenin, or mixtures thereof.

[0094] In one embodiment, the one or more pharmaceutical lubricants comprise sodium stearyl fumarate. In another embodiment, the one or more pharmaceutical lubricants consist of sodium stearyl fumarate.

[0095] In one embodiment, the one or more pharmaceutical lubricants include one or more behenic acid esters of glycerin (ie, one or more of glyceryl dibehenate, tribehenin, and glyceryl behenate).

[0096] In one embodiment, the formulations provided herein include a compression aid. In a further embodiment, the compression aid is dicalcium phosphate dihydrate, dibasic calcium phosphate dihydrate (DCPD). DCPD is used in tablet formulations as an excipient and as a source of calcium and phosphorus in dietary supplements.

[0097] In one embodiment, the compositions described herein include a compression aid, such as DCPD, in an amount of about 10 to about 30 wt%, including about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, or about 24 wt%. In a further embodiment, the compression aid is present at about 20% (wt%).

[0098] In one embodiment, the compositions described herein include a compression aid, e.g., DCPD, in an amount of about 10 to about 25 wt%, about 10 to about 20 wt%, about 10 to about 15 wt%, about 15 to about 25 wt%, or about 20 to about 25 wt%. In a further embodiment, one or more pharmaceutical lubricants in the composition are glycerol behenate. In a further embodiment, one or more pharmaceutical glidants in the composition include silicon dioxide. In a further embodiment, one or more pharmaceutical disintegrants in the composition are sodium starch glycolate. In a further embodiment, one or more pharmaceutical diluents include microcrystalline cellulose. In yet a further embodiment, the API in the composition is Compound A or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment, the compositions provided herein are tablets and have a film coating. The film coating can be applied using conventional methods known to those skilled in the art. Functional coatings can be used, for example, to provide protection against moisture ingress or light degradation, or to color the formulation. Additionally, functional coatings can be used to modify or control the release of the API from the composition.

[0100] Modified and controlled release coatings are known to those skilled in the art and include, for example, enteric coatings (e.g., cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid / methyl methacrylate 30 copolymer, shellac, and mixtures thereof), reverse enteric coatings (e.g., maltrin, aminoalkyl methacrylate copolymers available under the trade name Eudragit® (Type El 00 or EPO), polyvinyl acetal diethylaminoacetate, e.g., AEA® available from Sankyo Co., Ltd. (Tokyo, Japan); and mixtures thereof), and water-insoluble polymer coatings (e.g., ethyl cellulose, cellulose acetate, cellulose triacetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic acid-methyl methacrylate copolymers (e.g., Eudragit RL, RS, and NE30D), and mixtures thereof).

[0101] Suitable coatings, e.g., film coatings, that can be applied to compositions according to the present disclosure include film-forming agents, such as sugars, or more particularly film-forming polymers. Suitable sugar coatings are well known to those skilled in the art and can be, for example, sucrose or lactose.

[0102] In one embodiment, the film coating comprises hypromellose, polyethylene glycol, titanium dioxide, and a mixture of red, yellow, and black iron oxides, such as the mixture sold under the trade name Aquarius Prime Brown BAP 312542 (Ashland).

[0103] Other suitable film coatings are commercially available as concentrates that can be diluted with water and, optionally, a cellulose ether such as HPMC and a plasticizer such as polyethylene glycol before application to the composition. Such concentrates include Opaspray from Colorcon. TMCoatings, e.g., Opaspray TM Brown M-1-25092 and Opaspray Yellow M-1-22842.

[0104] Suitable film-forming agents include, for example, film-forming polymers, such as cellulose ethers, esters, and mixtures of ethers and esters, including esters of water-soluble cellulose ethers, such as hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose acetate succinate, or hydroxypropyl methylcellulose phthalate; film-forming acrylic polymers, such as methacrylate-methyl methacrylate copolymers; and film-forming vinyl polymers, such as polyvinyl alcohol or polyvinyl acetate phthalate. In some embodiments, the film-forming polymer is a water-soluble film-forming polymer, particularly a water-soluble cellulose ether, such as hydroxypropyl methylcellulose (particularly a hydroxypropyl methylcellulose having a dynamic viscosity of 2 to 18 cP (measured in a 2% w / v solution at 20°C), selected from, for example, grades 1828, 2208, 2906, and especially 2910, as defined above). The amount of film-forming agent used depends on the desired properties of the film coating, and the specific amount necessary to achieve the desired properties can be selected by one skilled in the art. Generally, the film-forming agent is present in an amount of 40-90% by weight of the film coating, for example, 50-80% by weight of the film coating. In certain embodiments, the film-forming agent is typically present at about 0.5-5% by weight of the formulation. In other embodiments, the film-forming agent is present at about 2.5-5% by weight of the formulation.

[0105] Optionally, the film coating contains additional ingredients such as plasticizers, colorants, dispersing aids, and opacifiers. Plasticizers can be used to improve the flexibility and durability of the film and the adhesive properties of the film coating. Suitable plasticizers include, for example, glycerin, acetylated monoglycerides, citric acid esters (e.g., triethyl citrate), propylene glycol, polyethylene glycols (e.g., polyethylene glycols having a molecular weight of 200 to 500, particularly 300), triacetin (glycerol triacetate), triglycerides (e.g., castor oil), or phthalic acid esters (e.g., diethyl phthalate). Generally, when used, plasticizers are present in an amount of 1 to 20% by weight, e.g., 5 to 15% by weight, of the film coating.

[0106] Suitable opacifiers and colorants are well known and include, for example, titanium dioxide, ferric oxides (eg, iron oxide).

[0107] Suitable dispersing aids include, for example, talc.

[0108] In some embodiments, the film coating comprises: (i) 50 to 100 (e.g., 50 to 80) parts of a water-soluble cellulose ether (e.g., hydroxypropyl methylcellulose, in particular hydroxypropyl methylcellulose having a dynamic viscosity of 2 to 18 cP (measured in a 2% w / v solution at 20°C), e.g., grades 2910, 1828, 2208, or 2906 as defined above having a dynamic viscosity of 5 to 7 cP); (ii) 0 to 25 (e.g., 5 to 20) parts of a plasticizer (e.g., polyethylene glycol, e.g., polyethylene glycol having a molecular weight of 200 to 500); and (iii) 0 to 50 (especially 0 to 30) parts in total of opacifiers (e.g., titanium dioxide), colorants (e.g., iron oxides), and dispersing agents where all parts are by weight and the total of parts (i)+(ii)+(iii)=100.

[0109] The coating may, for example, comprise 0.5-10 wt % of the composition, such as about 1-6%, or about 2-5 wt %.

[0110] One or more of the compositions provided herein, in one embodiment, are used to treat obstructive airway diseases in a patient in need thereof. Obstructive airway diseases, in one embodiment, include asthma (including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced asthma (including aspirin-induced and NSAID-induced), and dust asthma), both intermittent and persistent, and of all severities, as well as other causes of airway hyperresponsiveness; chronic obstructive pulmonary disease (COPD); bronchitis (including infectious bronchitis and eosinophilic bronchitis); emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; alpha-1 antitrypsin deficiency; farmer's lung and related diseases; hypersensitivity pneumonitis; pulmonary fibrosis (idiopathic fibrosing alveolitis, idiopathic interstitial pneumonia, antineoplastic therapy, and chronic infections (tuberculosis and aspergillosis, and and fibrosis associated with chronic or chronic respiratory tract infections (including other fungal infections); complications of lung transplantation; vasculitic and thrombotic disorders of the pulmonary vasculature and pulmonary hypertension; antitussive effects, including the treatment of chronic cough associated with inflammatory and secretory conditions of the airways and iatrogenic cough; acute and chronic rhinitis (including rhinitis medicamentosa and vasomotor rhinitis); perennial and seasonal allergic rhinitis (including rhinitis neuropathica (hay fever)); nasal polyposis; acute viral infections (including the common cold and infections caused by respiratory syncytial virus, influenza, coronaviruses (including SARS), and adenoviruses), acute lung injury, adult respiratory distress syndrome (ARDS), and exacerbations of each of the above-mentioned respiratory disease conditions. In one embodiment, the composition comprises an effective amount of Compound A.

[0111] In one embodiment, the treatment is treatment of asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, particularly chronic asthma or refractory asthma (e.g., late-onset asthma or airway hyperresponsiveness)), chronic obstructive pulmonary disease (COPD) or allergic rhinitis.

[0112] In one embodiment, the compositions provided herein can be orally administered to a patient with bronchiectasis in need of treatment. The bronchiectasis can be in a patient with cystic fibrosis or in a patient without cystic fibrosis (often referred to as "bronchiectasis unrelated to cystic fibrosis" or "non-CF bronchiectasis"). The administration schedule can be determined by the user of the method, e.g., a prescribing physician. In one embodiment, administration is once daily. In another embodiment, administration is twice daily. In another embodiment, administration is every other day, three times a week, or four times a week.

[0113] Non-CF bronchiectasis has been reported to result from or be associated with numerous etiologies ranging from genetic disorders to retained airway foreign bodies, and has been reported to be present in patients with systemic diseases, common respiratory diseases such as chronic obstructive pulmonary disease (COPD), and uncommon diseases such as sarcoidosis (Chang and Bilton (2008). Thorax 63, pp. 269-276, incorporated herein by reference in its entirety for all purposes).

[0114] Bronchiectasis is considered a pathological endpoint resulting from many disease processes and is a persistent or progressive condition characterized by dilated, thick-walled bronchi. Symptoms range from intermittent episodes of expectoration and infection localized to affected lung regions to persistent daily expectoration of often copious amounts of purulent sputum. Bronchiectasis may be associated with other nonspecific respiratory symptoms. Without wishing to be bound by theory, the pathological process underlying bronchiectasis has been reported as damage to the airways resulting from an event or series of events in which inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, Vol. 65(Suppl 1), incorporated herein by reference in its entirety for all purposes). Methods of treating bronchiectasis using compounds of Formula (I) are described in U.S. Patent Application Publication No. 2018 / 0028541, incorporated herein by reference in its entirety for all purposes.

[0115] The term "treating" in one embodiment includes (1) preventing or delaying the onset of clinical symptoms of the state, disorder, or condition in a patient who may be afflicted with or predisposed to the state, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the state, disorder, or condition; (2) inhibiting the state, disorder, or condition (e.g., arresting, reducing, or delaying the onset of at least one clinical or subclinical symptom of the disease, or in the case of maintenance treatment, its recurrence); (3) alleviating the condition (e.g., causing regression of the state, disorder, or condition, or at least one clinical or subclinical symptom thereof). In one embodiment, the clinical symptom is pulmonary exacerbation and / or (4) prevention of bronchiectasis, e.g., non-CF bronchiectasis.

[0116] Prevention is expected to be particularly relevant to the treatment of individuals who have suffered from a previous episode of bronchiectasis or are otherwise considered at high risk for bronchiectasis. Accordingly, in one embodiment of the present invention, a method is provided for providing prevention of bronchiectasis to a patient in need thereof. In one embodiment, the patient in need thereof has suffered from a previous episode of bronchiectasis or is at high risk of being diagnosed with bronchiectasis. The method comprises administering to the patient one of the compositions provided herein. In a further embodiment, the compound of formula (I) is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide or a pharmaceutically acceptable salt thereof.

[0117] As used herein, a "pulmonary exacerbation" is three or more of the following symptoms exhibited by a patient for at least 48 hours: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased shortness of breath and / or decreased exercise tolerance; (5) fatigue and / or malaise; and (6) hemoptysis. In one embodiment, three or more symptoms result in a physician's decision to prescribe an antibiotic to the symptomatic patient.

[0118] In one embodiment, treatment by administering a composition provided herein comprises increasing the length of time to pulmonary exacerbation compared to the length of time to pulmonary exacerbation in an untreated bronchiectasis patient. For example, in some embodiments, the length of time to pulmonary exacerbation is increased by at least about 20 days compared to the length of time to pulmonary exacerbation in an untreated bronchiectasis patient. In other embodiments, the length of time to pulmonary exacerbation is increased by about 20 to about 100 days compared to the length of time to pulmonary exacerbation in an untreated bronchiectasis patient. In other embodiments, the length of time to pulmonary exacerbation is increased by about 25 to about 100 days, about 30 to about 100 days, about 35 to about 100 days, or about 40 to about 100 days compared to the length of time to pulmonary exacerbation in an untreated bronchiectasis patient. In other embodiments, the increase is about 25 to about 75 days, about 30 to about 75 days, about 35 to about 75 days, or about 40 to about 75 days, compared to the length of time to pulmonary exacerbation in untreated bronchiectasis patients. In other embodiments, the increase in time to pulmonary exacerbation is about 30 to about 60 days, compared to the length of time to pulmonary exacerbation in untreated bronchiectasis patients. In further embodiments, the compound in the composition is an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0119] In one embodiment, the increase in time between pulmonary exacerbations comprises an increase of about 1 day, about 3 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks, or an increase of at least about 1 day, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, or at least about 6 weeks. In another embodiment, the increase comprises an increase of about 20 days to about 100 days, or about 30 days to about 100 days, about 20 days to about 75 days, or about 20 days to about 50 days, or about 20 days to about 40 days. In a further embodiment, the compound in the composition is an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0120] In yet another embodiment, a method for treating bronchiectasis, e.g., non-CF bronchiectasis, is provided, comprising administering one of the compositions provided herein to a patient in need of treatment. In one embodiment, the compound is administered once daily. Treatment includes reducing the rate of pulmonary exacerbations compared to the rate of pulmonary exacerbations experienced by the patient before treatment, or compared to untreated patients with bronchiectasis. The rate of pulmonary exacerbations can be calculated by dividing the number of exacerbations by a specific period, such as 1 day, 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months, or about 24 months. The reduction in exacerbation rate, in one embodiment, is a reduction of about 15%, about 20%, about 25%, about 30%, about 35%, about 40% or about 50%, about 55%, about 60%, about 65%, about 70%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 50%, at least about 70% compared to the rate of pulmonary exacerbations experienced by the patient prior to treatment or compared to untreated bronchiectasis patients.

[0121] In another embodiment, the reduction in exacerbation rate is, in one embodiment, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 50%. In one embodiment, the compound in the composition is an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0122] In yet another embodiment, a method for treating bronchiectasis, e.g., non-CF bronchiectasis, is provided, comprising administering one of the compositions provided herein to a patient in need thereof. In one embodiment, the compound is administered once daily. The method includes reducing the duration of pulmonary exacerbations compared to the duration of pulmonary exacerbations experienced by the patient prior to treatment, or compared to an untreated bronchiectasis patient. The reduction in the duration of pulmonary exacerbations is a reduction in duration of about 12 hours, about 24 hours, about 48 hours, or about 72 hours, at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about 96 hours, at least about 120 hours, at least about 144 hours, or at least about 168 hours. In another embodiment, the reduction in the duration of pulmonary exacerbations is a reduction in duration of about 6 hours to about 96 hours, about 12 hours to about 96 hours, about 24 hours to about 96 hours, about 48 hours to about 96 hours, or about 48 hours to about 168 hours. In yet another embodiment, the reduction in the duration of pulmonary exacerbations is by about 1 day to about 1 week, by about 2 days to about 1 week, by about 3 days to about 1 week, by about 4 days to about 1 week, by about 5 days to about 1 week, or by about 6 days to about 1 week. In yet another embodiment, the reduction in the duration of pulmonary exacerbations is by about 1 day to about 2 weeks, by about 2 days to about 2 weeks, by about 4 days to about 2 weeks, by about 6 days to about 2 weeks, by about 8 days to about 2 weeks, or by about 10 days to about 2 weeks.

[0123] In other embodiments, the reduction in duration is from about 6 hours to about 96 hours, from about 12 hours to about 96 hours, from about 24 hours to about 96 hours, from about 48 hours to about 96 hours, or from about 48 hours to about 168 hours.

[0124] In one embodiment, the reduction in duration is the average reduction in exacerbations experienced during treatment. In a further embodiment, the composition comprises an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0125] In another embodiment, a method for treating bronchiectasis, e.g., non-CF bronchiectasis, is provided, comprising administering a composition provided herein to a patient in need of treatment. In one embodiment, the compound is orally administered once daily. In this embodiment, treatment comprises reducing the number of pulmonary exacerbation-related hospitalizations in the patient compared to the number of pulmonary exacerbation-related hospitalizations in the patient before treatment or compared to untreated bronchiectasis patients. In one embodiment, the number of hospitalizations is measured over a treatment period and compared to the same period in pre-treatment or untreated bronchiectasis patients. In a further embodiment, the compound in the composition is an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0126] In one embodiment of the methods provided herein, a method is provided for treating bronchiectasis, e.g., non-CF bronchiectasis, comprising administering to a patient in need thereof one of the compositions provided herein, wherein the method comprises increasing the patient's lung function compared to the patient's lung function before treatment or compared to an untreated bronchiectasis patient. In one embodiment, the compound in the composition is an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0127] In one embodiment, the increase in lung function is measured by spirometry.

[0128] In one embodiment, increased lung function includes increasing the forced expiratory volume in 1 second (FEV1) after a bronchodilator, increasing the forced vital capacity (FVC), increasing the peak expiratory flow rate (PEFR), or increasing the forced expiratory flow rate of 25% to 75% of the FVC (FEF25-75) compared to the respective values ​​before treatment or compared to untreated bronchiectasis patients. In one embodiment, the increase is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of the respective values. In one embodiment, the increase is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In yet another embodiment, the increase is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20%. In yet another embodiment, the increase is about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.

[0129] In one embodiment, e.g., FEV1, PEFR, or FEF 25-75 Assessment of pulmonary function via measurements includes comparing the patient's pulmonary function before treatment, e.g., immediately before treatment, with a time point during treatment, an average of measurements taken during treatment, or after treatment has ended.

[0130] As provided herein, in one embodiment, treatment according to the methods of the invention includes improving a patient's lung function, wherein the lung function is measured by spirometry. Spirometry is a physiological test that measures how an individual inhales or exhales large volumes of air. The primary signal measured by spirometry can be volume or flow. In the methods described herein, spirometry (e.g., FEV1, FVC, PEFR, and FEF) is used to measure the lung function of a patient. 25-75Pulmonary function tests (PFTs) are performed according to American Thoracic Society (ATS) / European Respiratory Society (ERS) standards, e.g., as described by Miller et al. (Miller et al. (2005). Standardization of Spirometry. Eur. Respir. J. 26, pp. 319-38, incorporated herein by reference in its entirety for all purposes).

[0131] In one embodiment, the spirometer is capable of accumulating volume for 15 seconds or more, e.g., 20 seconds or more, 25 seconds or more, 30 seconds or more, 35 seconds or more. In one embodiment, the spirometer is capable of accumulating volume for 0-14 L s -1 It is capable of measuring volumes of ≥ 8 L with an accuracy of at least ±3% of reading or ±0.050 L, whichever is greater, at flow rates between 14 L s (BTPS). -1 The total resistance to airflow in the spirometer is <1.5 cmH2O L -1 ·s -1 (0.15kPa·L -1 ·s -1 ). In one embodiment, the total resistance of the spirometer is measured, including any tubing, valves, pre-filters, etc. that may be inserted between the patient and the spirometer. For devices that exhibit changes in resistance due to water vapor condensation, in one embodiment, the accuracy requirements of the spirometer are met for up to eight consecutive FVC maneuvers performed in 10 minutes under BTPS (body temperature, ambient pressure, saturated with water vapor) conditions, with no inspiration from the device.

[0132] With respect to the forced expiratory techniques described herein, in one embodiment, the range and precision recommendations as set forth in Table 6 of Miller et al. (Miller et al. (2005). Standardization of Spirometry. Eur. Respir. J. 26, pp. 319-38, incorporated by reference in its entirety for all purposes) are met.

[0133] In one embodiment, the improvement in pulmonary function is an improvement in forced vital capacity (FVC), i.e., the maximum volume of air exhaled from maximal inspiration with a maximal forced effort, measured in liters at body temperature and ambient pressure saturated with water vapor (BTPS).

[0134] "Forced vital capacity" (FVC) refers to the volume of gas exhaled during forced expiration, beginning at a position of full inspiration and ending at a position of full expiration, and is one measure of therapeutic efficacy. In one embodiment of the methods provided herein, improving the patient's pulmonary function comprises improving the patient's FVC compared to the patient's FVC before treatment or compared to an untreated patient with bronchiectasis. In one embodiment, the FVC of a treated patient is about 1% higher, about 2% higher, about 3% higher, about 4% higher, about 5% higher, about 6% higher, about 7% higher, about 8% higher, about 9% higher, about 10% higher, about 11% higher, about 12% higher, about 13% higher, about 14% higher, about 15% higher, about 16% higher, about 17% higher, about 18% higher, about 19% higher, about 20% higher, about 25% higher, about 30% higher, about 35% higher, about 40% higher, about 45% higher, about 50% higher, about 55% higher, about 60% higher, about 65% higher, about 70% higher, about 75% higher, about 80% higher, about 85% higher, or about 90% higher compared to the patient's FVC before treatment or compared to an untreated patient with bronchiectasis.

[0135] The FVC maneuver can be performed according to procedures known to those skilled in the art. Briefly, the three distinct phases of the FVC maneuver are (1) maximal expiration; (2) the "blast" of expiration; and (3) complete expiration, continuing until the end of the test (EOT). The maneuver can be performed via either a closed-circuit or open-circuit technique. In either case, the subject inhales rapidly and completely, pausing for less than one second at total lung capacity (TLC). The subject then exhales maximally until they are unable to expel air while maintaining an upright posture. Exhalation begins with a "blast" of air from the lungs, followed by encouragement to exhale completely. Intensive coaching of the subject continues for a minimum of three maneuvers.

[0136] In one embodiment, improving pulmonary function is an improvement compared to pulmonary function immediately prior to treatment or compared to an untreated bronchiectasis patient. In a further embodiment, improving pulmonary function comprises increasing the patient's forced expiratory volume in one second (FEV1) compared to the patient's FEV1 before treatment or compared to the FEV1 of an untreated bronchiectasis patient. FEV1 is the volume of gas exhaled in a given time (typically 1 second, i.e., FEV1) from the start of a forced vital capacity maneuver (Quanjer et al. (1993). Eur. Respir. J. 6, Suppl. 16, pp. 5-40, incorporated herein by reference in its entirety for all purposes).

[0137] In one embodiment, the increase in FEV1 is at least about 5%, for example, an increase of about 5% to about 50%, or about 10% to about 50%, or about 15% to about 50%. In another embodiment, the FEV1 of the treated patient is about 1% more, about 2% more, about 3% more, about 4% more, about 5% more, about 6% more, about 7% more, about 8% more, about 9% more, about 10% more, about 11% more, about 12% more, about 13% more, about 14% more, about 15% more, about 16% more, about 17% more, about 18% more, about 19% more, about 20% more, about 25% more, about 30% more, about 35% more, about 40% more, about 45% more, about 50% more, about 55% more, about 60% more, about 65% more, about 70% more, about 75% more, about 80% more, about 85% more, or about 90% more compared to the FEV1 of the patient before treatment or compared to an untreated patient with bronchiectasis.

[0138] In another embodiment, improving lung function comprises increasing the patient's FEV1 by about 25 mL to about 500 mL, or about 25 mL to about 250 mL, or about 50 mL to about 200 mL compared to the patient's FEV1 before treatment or compared to an untreated bronchiectasis patient.

[0139] In one embodiment, improved pulmonary function is measured by measuring a mean forced expiratory flow (FEF) of 25% to 75% of the patient's FVC before treatment. 25-75 ) (also called peak mid-expiratory flow) or compared with untreated bronchiectasis patients. 25-75 Measurement depends on the validity of the FVC measurement and the level of expiratory effort. FEF 25-75 The index is taken from the blow at which the sum of FEV1 and FVC is greatest.

[0140] In one embodiment, the improved lung function comprises an improvement in the patient's peak expiratory flow rate (PEFR), which is compared to the PEFR immediately before treatment or compared to an untreated bronchiectasis patient. PEFR measures the fastest air velocity a subject can exhale. In one embodiment, the PEFR of the treated patient is about 1% greater, about 2% greater, about 3% greater, about 4% greater, about 5% greater, about 6% greater, about 7% greater, about 8% greater, about 9% greater, about 10% greater, about 11% greater, about 12% greater, about 13% greater, about 14% greater, about 15% greater, about 16% greater, about 17% greater, about 18% greater, about 19% greater, about 20% greater, about 25% greater, about 30% greater, about 35% greater, about 40% greater, about 45% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70% greater, about 75% greater, about 80% greater, about 85% greater, or about 90% greater than the PEFR of the patient before treatment or compared to an untreated patient with bronchiectasis.

[0141] In yet another embodiment of the present invention, there is provided a method for treating bronchiectasis comprising administering to a patient in need thereof one of the compositions provided herein, wherein the treatment comprises increasing the patient's quality of life (QOL) compared to the patient's quality of life before treatment, e.g., compared to a baseline value. In a further embodiment, the compound in the composition is an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0142] In one embodiment, a patient's quality of life is assessed using the Quality of Life - Bronchiectasis (QOL-B) questionnaire. The QOL-B questionnaire is a validated, self-administered patient-reported outcome (PRO) that assesses symptoms, function, and health-related quality of life in subjects with bronchiectasis (Quittner et al. (2014). Chest 146(2), pp. 437-448; Quittner et al. (2015) Thorax 70(1), pp. 12-20 (each incorporated by reference in its entirety for all purposes)). The QOL-B includes 37 items across eight domains: respiratory symptoms, physical function, role function, emotional function, social function, vitality, health perceptions, and treatment burden.

[0143] In another embodiment, the patient's quality of life is assessed by the Leicester Cough Questionnaire (LCQ). In one embodiment, improvement in quality of life is a change from baseline (pre-treatment) in the patient's LCQ score. The LCQ is a validated questionnaire that assesses cough in quality of life in subjects with bronchiectasis and other conditions in which cough is a common symptom (Murray et al. (2009). Eur Respir J. 34: 125-131, incorporated by reference in its entirety for all purposes). The LCQ contains 19 items and takes 5-10 minutes to complete. Each item assesses a symptom or symptom impact over the past two weeks on a 7-point Likert scale. Scores for the three domains (physical, psychological, and social) are calculated as the mean of each domain (range 1-7). The domain scores are summed to calculate a total score (range 3-21). Higher scores indicate better quality of life.

[0144] In another embodiment, the patient's quality of life is assessed by the St. George's Respiratory Questionnaire (SGRQ). In one embodiment, the improvement in quality of life is the change from baseline (pre-treatment) in the patient's SGRQ score. The St. George's Respiratory Questionnaire (SGRQ) is a self-administered questionnaire of 50 questions designed to measure and quantify health-related well-being in subjects with chronic airflow limitation (Jones et al. (1991). Respir Med. 85 Suppl B 25-31; discussion 33-7, incorporated herein by reference in its entirety for all purposes). The SGRQ assesses health-related quality of life by assessing three health domains: (1) symptoms (distress caused by respiratory symptoms), (2) activity (impact of impairment on mobility and physical activity), and (3) impact (impact of disease on factors such as employment, personal health care, and medication needs). It has been shown to correlate well with established measures of the three domains in subjects with asthma and COPD. It has also been validated for use in the NCFBE. A composite total score is derived as the sum of the symptom, activity, and impact domain scores, with 0 being the best possible score and 100 being the worst possible score. A 4-unit reduction in score is generally recognized as a clinically meaningful improvement in quality of life.

[0145] In another embodiment of the method for treating bronchiectasis provided herein, one of the compositions provided herein is administered to a patient in need thereof, wherein the method comprises reducing the active neutrophil elastase (NE) sputum concentration compared to the patient's NE sputum concentration before treatment. In one embodiment, the composition comprising a compound of Formula (I) is administered by oral administration. In a further embodiment, administration is once daily, every other day, twice weekly, three times weekly, or four times weekly. In a further embodiment, the compound in the composition is an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0146] In one embodiment, the reduction in active NE sputum concentration comprises a reduction of about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%. In another embodiment, the reduction in active NE sputum concentration comprises a reduction of at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%.

[0147] In yet another embodiment of the method for treating bronchiectasis provided herein, one of the compositions provided herein is administered to a patient in need of such treatment, wherein the method comprises lightening the color of the patient's sputum, as compared to the color of the patient's sputum before treatment, as measured by the Murray 2009 sputum color chart (Murray et al. (2009). Eur Respir J. 2009; 34:361-364, incorporated by reference in its entirety for all purposes). In one embodiment, the composition comprising a compound of Formula (I) is administered by oral administration. In a further embodiment, administration is once daily, every other day, twice weekly, three times weekly, or four times weekly. In one embodiment, the compound in the composition is an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0148] In one embodiment, the color lightening is a lightening by a single shade. For example, in one embodiment, the lightening is from purulent (dark yellow and / or dark green) to mucopurulent (pale yellow and / or pale green). In another embodiment, the lightening is from mucopurulent (pale yellow and / or pale green) to mucous (clear).

[0149] In another embodiment, the color change is a two-tone lightening, ie, the lightening is from purulent (dark yellow and / or dark green) to mucous (clear).

[0150] If the patient is unable to produce sputum on their own, sputum induction is performed. In one embodiment, sputum induction is initiated via patient nebulization of saline. The percentage of saline, e.g., 3%, 7%, 10%, or 13%, is determined based on the user's method preference. The selected saline solution is placed in a nebulizer, and the subject is in a seated or semi-Fowler position. In one embodiment, the subject wears a nose clip throughout the nebulization. The subject inhales the saline mist by breathing slowly and deeply through the nebulizer mouthpiece. The subject is reminded to take slow, deep breaths rather than rapid breaths, and to pause at peak inspiration to allow particle deposition. In one embodiment, the nebulization time is 10 minutes.

[0151] At the end of nebulization, the subject is instructed to take several deep breaths, swallow any excess saliva, and attempt to cough up a sputum sample. The subject is encouraged to cough forcefully using the deep coughing method and / or the "huffing" coughing technique. All sputum is placed in the specimen container. If the amount of sputum collected is insufficient, e.g., less than 1 mL, less than 2 mL, or less than 3 mL, this procedure can be repeated.

[0152] In one embodiment, the compositions provided herein can be orally administered to a patient in need of treatment for ANCA-associated vasculitis (e.g., GPA or MPA). Methods for treating ANCA-associated vasculitis (e.g., GPA or MPA) using compounds of Formula (I) are described in U.S. Application No. 16 / 269,191, which is incorporated by reference in its entirety for all purposes.

[0153] GPA is a rare systemic autoimmune necrotizing granulomatous inflammation of small blood vessels and a systemic vasculitis (Pagnoux (2016). Eur J Rheumatol. 3(3), pp. 122-33; Schoenermarck et al. (2015). Nephrol Dial Transplant. 2015;30(Suppl1): i46-52 (each incorporated by reference in its entirety for all purposes)). It most commonly affects the upper and / or lower respiratory tract, kidneys, skin, and peripheral nerves. Neutrophils and anti-neutrophil cancer (ANCA) are involved in the pathogenesis of GPA. In most patients with GPA, ANCA bind to membrane-bound PR3 (mPR3) and cause neutrophil activation with the release of ROS and proteases, including active NSPs (PR3, NE, and CatG). This extracellular proteolytic activity contributes to the endothelial vascular necrosis observed in GPA patients (Jerke et al. (2015). Kidney Int. 88(4):764-775; Kettritz (2016). Immunol Rev. 273(1): 232-248, each incorporated by reference in its entirety for all purposes).

[0154] If left untreated, GPA is a severe, progressive disease that can lead to death from multiple organ failure (Millet et al. (2013). Ann Rheum Dis. 72(8):1273-9; Yates and Watts (2017). Clin Med (Lond). 17(1):60-64, each incorporated by reference in its entirety for all purposes). Standard treatments include the combination of cytotoxic immunosuppressants such as cyclophosphamide and more recently rituximab, with high-dose glucocorticoids. Despite treatment, disease recurrence is common (Guillevin et al. (2014). N Engl J Med. 371(19): 1771-80; Jayne et al. (2003). N Engl J Med. 2003;349(1):36-44; Pagnoux et al. (2008). N Engl J Med. 359(26):2790-2803 (each incorporated by reference in its entirety for all purposes)), and mortality remains high (Heijl et al. (2017). RMD open; Volume 3, Issue 1, p:e000435; Pearce et al. (2017). Rheumatology (Oxford). 56(4):589-96 (each incorporated by reference in its entirety for all purposes)). Furthermore, current therapies have a narrow margin of safety due to systemic toxicity. In summary, there remains a high unmet need for adequate treatment of GPA, particularly for maintenance of remission. This outstanding unmet need highlights the need to develop novel treatment strategies, such as those that can be achieved by the methods of the present invention.

[0155] In some embodiments, the methods provided herein use a reversible inhibitor of lysosomal cysteine ​​protease dipeptidyl peptidase 1 (DPP1), represented by Formula (I), in a method for treating ANCA-associated vasculitis, including, but not limited to, GPA and / or MPA. Without wishing to be bound by theory, it is believed that the compounds of Formula (I) administered by the methods provided herein have beneficial effects through inhibition of PR3 activation via upstream inhibition of DPP1. Without wishing to be bound by theory, inhibition of DPP1 reduces the amount of activated NSPs available for release during neutrophil degranulation. Furthermore, inhibition of PR3 activation subsequently results in a lack of PR3 interaction and expression on the neutrophil membrane surface (mPR3). Reduced mPR3 may then limit targets to which PR3-specific ANCA can bind, thereby attenuating neutrophil activation. Furthermore, without wishing to be bound by theory, because autoantibodies in MPA patients bind to surface PR3 and / or stimulate NSP release and subsequent tissue damage, the pharmacological effect of Compound A on neutrophils may treat MPA and other myeloperoxidase (MPO)-ANCA-associated disorders by reducing NSP activity and decreasing tissue damage following neutrophil degranulation.

[0156] Three NSPs, abundantly secreted into the extracellular milieu upon neutrophil activation at inflammatory sites, are thought to act in combination with reactive oxygen species to aid in the degradation of phagocytosed microorganisms within phagolysosomes. Because some of the released proteases remain bound in an active form to the outer surface of the plasma membrane, both soluble and membrane-bound NSPs can regulate the activity of various biomolecules, such as chemokines, cytokines, growth factors, and cell surface receptors. Regulation is thought to occur by converting the respective biomolecules to their active forms or by degrading the biomolecules through proteolytic cleavage. Secreted proteases can stimulate mucus secretion and inhibit mucociliary clearance, but can also activate lymphocytes and cleave apoptotic and adhesion molecules (Bank and Ansorge (2001). J Leukoc Biol. 69, pp. 197-206; Pham (2006). Nat Rev Immunol. 6, pp. 541-550; Meyer-Hoffert (2009). Front Biosci. 14, pp. 3409-3418; Voynow et al. (2004). Am J Physiol Lung Cell Mol Physiol. 287, pp. L1293-302 (each incorporated by reference in its entirety for all purposes)).

[0157] In some embodiments, the methods of treatment provided herein comprise administering to a patient in need of treatment for ANCA-associated vasculitis a composition comprising an effective amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the composition comprising an effective amount of a compound represented by Formula (I) is administered orally. In one embodiment, the compound is Compound A or a pharmaceutically acceptable salt thereof. In a further embodiment, administration is once daily, twice daily, once every other day, once every third day, once every third day, twice weekly, three times weekly, or four times weekly. In yet a further embodiment, administration is once daily. In yet a further embodiment, administration is orally once daily.

[0158] In one embodiment of the methods of treatment provided herein, treating a patient for ANCA-associated vasculitis comprises reducing the patient's Birmingham Vasculitis Activity Score (BVAS) compared to the BVAS before treatment (Suppiah et al. (2011). Rheumatology 50, pp. 899-905; Mukhtyar et al. (2009). "Modification and validation of the Birmingham Vasculitis Activity Score (version 3) ARD 2009 68:1827, each incorporated by reference in its entirety for all purposes). In one embodiment, such a reduction can be to zero, i.e., when treatment achieves remission of ANCA-associated vasculitis.

[0159] In another embodiment, treating a patient includes maintaining a BVAS score of 0, i.e., maintaining remission. The BVAS score measures disease activity in patients with various systemic vasculitis and scores abnormalities due to the presence of active vasculitis. Selga et al. (2006). Rheumatology 45, pp. 1276-1281 (incorporated by reference in its entirety for all purposes).

[0160] The BVAS assessment form includes 56 disease items characterized by nine groups and an "Other" section. Items on the BVAS assessment form are counted only if they are due to active vasculitis. The maximum possible score is 63. A score of 0 indicates disease remission, and a score of 1 or greater indicates an active disease state (Suppiah et al. (2011). Rheumatology 50, pp. 899-905 (incorporated herein by reference in its entirety for all purposes)).

[0161] In one embodiment, the ANCA-associated vasculitis is microscopic polyangiitis (MPA), and methods are provided for treating patients in remission of MPA and for maintaining remission in patients. The methods comprise administering to the patient a composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, remission is measured by a BVAS score of 0 before treatment and a BVAS score of 0 during or after treatment. In a further embodiment, the compound of Formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the composition is administered orally. In yet a further embodiment, administration is once daily, twice daily, once every other day, once every two days, once every three days, twice weekly, three times weekly, or four times weekly. In yet a further embodiment, administration is once daily. In one embodiment, administration is orally once daily.

[0162] In one embodiment, the ANCA-associated vasculitis is microscopic polyangiitis (MPA), and a method of treating a patient with MPA comprises reducing the patient's BVAS score from ≥1 to 0. The method comprises administering to the patient a composition comprising an effective amount of a compound of Formula (I). In a further embodiment, the compound of Formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the composition is administered orally. In yet a further embodiment, administration is once daily, twice daily, once every other day, once every third day, once every third day, twice weekly, three times weekly, or four times weekly. In yet a further embodiment, administration is once daily. In yet a further embodiment, administration is orally once daily.

[0163] In one embodiment, the ANCA-associated vasculitis is granulomatosis with polyangiitis (GPA), and a method for treating GPA in a patient in need thereof is provided. The patient may have active disease or be in remission, as measured, for example, by the Birmingham Vasculitis Activity Score specific for Wegener's Granulomatosis (BVAS / WG). Stone et al. (2001). A disease-specific activity index for Wegener's Granulomatosis. Arthritis & Rheumatism 44(4), pp. 912-920 (incorporated by reference in its entirety for all purposes).

[0164] The BVAS / WG assessment form includes: (1) 34 distinct disease items categorized into nine groups; (2) an "Other" section; (3) an asterisk for 15 significant items (i.e., items that constitute an immediate threat to the patient's life or vital organ function); (4) check boxes indicating new / worse or persistent disease; (5) a column for summing scores; (6) a section for specifying disease status; (7) a physician global assessment of disease activity (PGA); and (8) an administrative box containing information about the patient identification code and clinical center. Items on the BVAS / WG assessment form are counted only if they are attributable to active WG and not to damage from previously active WG or another medical condition. The BVAS / WG includes a categorical assessment that incorporates major and minor items in the definition of disease status. (Stone et al. (2001). Arthritis & Rheumatism 44(4), pp. 912–920 (incorporated herein by reference in its entirety for all purposes).) The four disease states are: (1) Severe disease / flare (the occurrence of significant new / worse events), (2) limited disease / flare (the occurrence of minor new / bad items); (3) persistent disease (presence of one or more items representing ongoing active disease since the patient's last evaluation), and (4) remission (no active disease, i.e., no new / worse and persistent items).

[0165] The BVAS / WG score is calculated by multiplying the number of major items (either new / worse or persistent) by 3 and adding this number to the total number of minor items. Thus, assuming there are no more than one major "other" item and no more than one minor "other" item, the maximum BVAS / WG score is 68. Stone et al. (2001). Arthritis & Rheumatism 44(4), pp. 912-920 (incorporated by reference in its entirety for all purposes).

[0166] For patients with active disease, in one embodiment, the method comprises decreasing the patient's Wegener's Granulomatosis-specific Birmingham Vasculitis Activity Score (BVAS / WG) score compared to the patient's BVAS / WG score before treatment. In a further embodiment, a composition comprising an effective amount of a compound of Formula (I) is administered orally. In a further embodiment, the compound of Formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In yet a further embodiment, administration is once daily, twice daily, once every other day, once every third day, once every third day, twice weekly, three times weekly, or four times weekly. In yet a further embodiment, administration is once daily. In yet a further embodiment, administration is orally once daily.

[0167] In one embodiment of the methods of treatment provided herein, treating GPA in a patient in need thereof is inhibiting GPA flare. GPA flare, as used herein, is defined in one embodiment as an increase in BVAS / WG score of 1 or more points. In a further embodiment, a composition comprising an effective amount of a compound of Formula (I) is orally administered to inhibit GPA flare. In a further embodiment, the compound of Formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In yet a further embodiment, administration is once daily, twice daily, once every other day, once every two days, once every three days, twice weekly, three times weekly, or four times weekly. In yet a further embodiment, administration is once daily. In yet a further embodiment, administration is orally once daily.

[0168] In another embodiment, the ANCA-associated vasculitis is granulomatosis with polyangiitis (GPA), and the patient is in GPA remission, e.g., as indicated by a BVAS / WG of 0. In one embodiment, the method comprises maintaining remission of GPA in the patient. The patient may be in remission for at least 30, 60, 90, or 120 days before treatment. The patient, in one embodiment, maintains remission during and / or after treatment. Remission, in one embodiment, can be measured 1, 7, 14, 30, 60, 90, or 120 days after treatment. A patient treated with one of the methods provided herein, in one embodiment, has previously received or is currently receiving treatment for GPA with an anti-CD20 antibody (e.g., rituximab), cyclophosphamide, or a steroid (e.g., a corticosteroid such as a glucocorticoid). In one embodiment, the compound of formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the composition is administered orally. In yet a further embodiment, administration is once daily, twice daily, once every other day, once every third day, once every third day, twice weekly, three times weekly, or four times weekly. In yet a further embodiment, administration is once daily. In yet a further embodiment, administration is orally once daily. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is orally administered once daily at about 10 mg to about 50 mg, or about 20 mg to about 45 mg, e.g., 10 mg, 25 mg, 30 mg, or 40 mg. In another embodiment, Compound A is orally administered at 40 mg once daily.

[0169] The therapeutic methods of the present disclosure can be used to treat patients in remission of GPA to maintain the remission. Alternatively, the methods of the present disclosure can be used to treat patients with active GPA to affect remission in the patient.

[0170] In some embodiments, therapeutic benefit is defined by the absence of recurrence or delayed recurrence compared to patients not treated via one of the methods provided herein. Recurrence may be severe or mild. Severe recurrence is defined as disease recurrence or worsening accompanied by: (1) BVAS / WG>0 and involvement of at least one major organ, (2) life-threatening symptoms, or (3) both (1) and (2). Mild recurrence is defined as disease recurrence or worsening accompanied by BVAS / WG>0 and not corresponding to severe recurrence but requiring mild intensification of treatment.

[0171] Other measures of efficacy include rate of flare, time to relapse, change from baseline in the Vasculitis Damage Index (VDI), systemic corticosteroid use based on total oral corticosteroid dose and duration of oral corticosteroid use, and change from baseline in quality of life as measured, for example, by the Short Form Health Survey Questionnaire (SF-36) score (described below).

[0172] The VDI is a standardized clinical measure of damage in systemic vasculitis. See Exley et al. (1997), Arthritis Rheum. 40(2):371-80 (incorporated herein by reference in its entirety). The VDI records the presence or absence of 64 damage items divided into 11 groups, including 10 organ systems and one general category: (1) musculoskeletal damage; (2) skin damage; (3) ear, nose, and throat damage; (4) pulmonary damage; (5) cardiovascular damage; (6) renal damage; (7) gastrointestinal damage; (8) peripheral vascular damage; (9) ocular damage; (10) neuropsychiatric damage; and (11) other damage.

[0173] The VDI score is a simple sum of the injury items and is cumulative, i.e., all previously scored items are carried over to each subsequent assessment, and therefore can only remain stable or increase.

[0174] In another embodiment of the therapeutic methods provided herein, treating a patient in need thereof comprises improving the patient's Short Form Health Survey (SF-36) score compared to the patient's pre-treatment score. The SF-36 measures eight scales: physical functioning (PF), role physical (RP), bodily pain (BP), general well-being (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). See, e.g., Lins and Carvalho (2016). SAGE Open Medicine 4, pp. 1-12 (incorporated by reference in its entirety for all purposes). In a further embodiment, a composition comprising an effective amount of a compound of Formula (I) is orally administered. In a further embodiment, the compound of Formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In yet further embodiments, administration is once daily, twice daily, once every other day, once every third day, once every third day, twice weekly, three times weekly, or four times weekly. In yet further embodiments, administration is once daily. In yet further embodiments, administration is oral once daily.

[0175] In another embodiment of the method for treating ANCA-associated vasculitis provided herein, a composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof. The method comprises reducing proteinase 3 (PR3) activity in leukocytes compared to the patient's PR3 activity in leukocytes before treatment. In a further embodiment, the compound of Formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the composition is orally administered to a patient in need thereof. In yet a further embodiment, administration is once daily, twice daily, once every other day, once every two days, once every three days, twice weekly, three times weekly, or four times weekly. In yet a further embodiment, administration is once daily. In yet a further embodiment, administration is orally once daily.

[0176] In one embodiment, PR3 activity is measured in white blood cells (e.g., neutrophils) obtained from the patient's whole blood. In another embodiment, PR3 activity is measured in white blood cells (e.g., neutrophils) obtained from the patient's sputum. In one embodiment, the reduction is about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%. In another embodiment, the reduction in PR3 activity comprises a reduction of at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. In one embodiment, the compound of Formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the composition is administered orally. In yet further embodiments, administration is once daily, twice daily, once every other day, once every third day, once every third day, twice weekly, three times weekly, or four times weekly. In yet further embodiments, administration is once daily. In yet further embodiments, administration is oral once daily.

[0177] In another embodiment of the methods of treatment provided herein, treating a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and reducing neutrophil cell surface expression of proteinase 3 in the patient compared to neutrophil cell surface expression of proteinase 3 before treatment. In one embodiment, the reduction comprises reducing PR3 neutrophil cell surface expression by about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%. In another embodiment, the reduction in proteinase 3 cell surface expression comprises a reduction of at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. In one embodiment, the compound of Formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In a further embodiment, the composition is orally administered.In yet a further embodiment, administration is once a day, twice a day, once every other day, once every two days, once every three days, twice a week, three times a week, or four times a week.In yet a further embodiment, administration is once a day.Therefore, in one embodiment, the composition is orally administered once a day.

[0178] In another embodiment of a method for treating ANCA-associated vasculitis (e.g., GPA or MPA), a composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment, wherein the method comprises decreasing neutrophil serine protease (NSP) activity in the patient's blood compared to the patient's NSP activity before treatment. In one embodiment, the compound of Formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the composition is administered orally. In one embodiment, administration is once daily, twice daily, once every other day, once every third day, once every third day, twice weekly, three times weekly, or four times weekly. In a further embodiment, administration is once daily. In a further embodiment, administration is orally once daily. In yet a further embodiment, the compound of Formula (I) is Compound A. The NSP can be neutrophil elastase (NE), proteinase 3 (PR3), and / or cathepsin G (CatG). In one embodiment, the reduction in NSP activity is about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%. In another embodiment, the reduction in NSP activity comprises reducing NSP activity by at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%.

[0179] In yet another embodiment of the methods of treating ANCA-associated vasculitis (e.g., GPA or MPA) provided herein, a composition provided herein comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient in need of such treatment, wherein the method comprises reducing the patient's ANCA blood level compared to the patient's ANCA blood level before treatment. In one embodiment, the composition is administered orally. In one embodiment, the compound of Formula (I) is Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the ANCA blood level is measured in the patient's plasma or serum. In a further embodiment, administration is once daily, twice daily, once every other day, once every two days, once every three days, twice weekly, three times weekly, or four times weekly. In one embodiment, administration is oral once daily.

[0180] In one embodiment, the method comprises reducing the patient's ANCA blood levels by about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%. In another embodiment, the reduction in ANCA blood levels comprises a reduction of at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. In one embodiment, the ANCA blood levels are measured in the patient's plasma or serum.

[0181] In one embodiment, decreasing the ANCA antibody concentration comprises decreasing the PR3ANCA antibody concentration in the patient compared to the PR3ANCA antibody concentration before treatment, hi another embodiment, decreasing the ANCA antibody concentration comprises decreasing the MPOANCA antibody concentration in the patient compared to the MPOANCA antibody concentration before treatment.

[0182] In yet another embodiment of the methods of treating ANCA-associated vasculitis (e.g., GPA or MPA) provided herein, a composition provided herein comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient in need of such treatment, wherein the method comprises reducing the number of CD19+ B cells in the patient compared to the number of CD19+ B cells in the patient before treatment. The compound of Formula (I), in one embodiment, is Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the composition is administered orally. In a further embodiment, administration is once daily, twice daily, once every other day, once every two days, once every three days, twice weekly, three times weekly, or four times weekly. In one embodiment, administration is once daily. In another embodiment, administration is orally once daily.

[0183] A composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may also be administered in conjunction with an additional compound used in the treatment of ANCA-associated vasculitis (e.g., GPA or MPA) by one of the methods described herein.

[0184] The additional compound is administered simultaneously, sequentially, or in admixture with a composition comprising a compound of Formula (I) for the treatment of ANCA-associated vasculitis.

[0185] The additional compound, in one embodiment, is an anti-TNFα antibody, such as infliximab, adalimumab, certolizumab pegol, and golimumab. In a further embodiment, the anti-TNFα antibody is infliximab.

[0186] In another embodiment, the additional compound is an anti-CD20 antibody, such as rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab, tiuxetan, tositumomab, and ublituximab. In a further embodiment, the anti-CD20 antibody is rituximab.

[0187] In yet another embodiment, the additional compound is a steroid. In a further embodiment, the steroid is a corticosteroid. In yet a further embodiment, the additional compound is a glucocorticoid.

[0188] In yet another embodiment, the additional compound is cyclophosphamide (CYC), alone or in combination with one or more glucocorticoids.

[0189] In one combination therapy embodiment, the compositions of the present disclosure are administered simultaneously or sequentially with one or more additional active ingredients selected from one or more of those provided above. For example, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered simultaneously or sequentially with an additional pharmaceutical composition for use as a medicament for treating ANCA-associated vasculitis. The additional pharmaceutical composition can be a medicament to which the patient may already be prescribed (e.g., an existing standard of care), which itself can be a composition comprising one or more active ingredients selected from those defined above. [Example]

[0190] The present invention will be further illustrated by reference to the following examples, however, it should be noted that these examples, like the above embodiments, are illustrative and should not be construed as limiting the scope of the invention in any way.

[0191] Example 1 - Preparation of film-coated tablets containing Compound A Film-coated tablets are manufactured using a dry granulation process followed by tablet compression. The tablets are then coated with a hypromellose-based film coat, which is a suspension of coating excipients in purified water. No organic solvents are used in the manufacturing process.

[0192] A brief summary of the core tablet manufacturing process, as well as a summary of the coating process, is provided below. Compound A is dry blended with microcrystalline cellulose, dibasic calcium phosphate dihydrate, sodium starch glycolate, and silicon dioxide. Compound A can be de-lumped prior to dispensing, if desired. The amount of Compound A is corrected for purity and the formulation adjusted accordingly at the expense of microcrystalline cellulose.

[0193] The blend is co-milled and then dry blended with intragranular glyceryl behenate. The lubricant can be loaded along with the same amount of microcrystalline cellulose that was omitted from the initial dry blending step.

[0194] Ribbons are produced by roller compacting the lubricated dry blend. The ribbons are then milled into granules. The granules are blended with extragranular glyceryl behenate and then compressed into tablet cores.

[0195] Finally, the tablet cores are coated with a non-functional aesthetic film coat. The film coating mixture is prepared by adding the coating excipients to purified water while mixing in an appropriately sized container. Spray process parameters can be adjusted throughout the process to achieve the target weight gain per tablet. Once completed, the tablets are dried and discharged into appropriate bulk containers.

[0196] The excipients in the tablet core and the corresponding standards are summarized in Table 1 below.

[0197] [Table 1]

[0198] The excipients included in the tablet coating and their corresponding standards are summarized in Table 2. These can be added as a proprietary composite, e.g., Aquarius Prime BAP312542.

[0199] [Table 2]

[0200] Example 2 - Excipient Compatibility with Compound A The excipient compatibility experiments were designed as a linear D-optimal design with two or more levels of qualitative factors. The formulations used in these experiments can be directly compressed into tablets. For dry processing, three factors were evaluated: binary filler combination, disintegrant selection, and lubricant selection. In the experimental design shown below (see Table 3), the effects of HPMC-based film coat and colloidal silicon dioxide addition were evaluated using repeat corners.

[0201] Two different filler combinations were selected for excipient compatibility: microcrystalline cellulose (MCC) combined with dicalcium phosphate dihydrate (DCPD) and mannitol (MAN) combined with MCC.

[0202] In this study, three disintegrants were evaluated: (i) croscarmellose sodium (internally cross-linked sodium carboxymethylcellulose or NaCMC), (ii) low-substituted hydroxypropyl cellulose (L-HPC), and (iii) sodium starch glycolate (NaSG). The amount of disintegrant was varied to obtain similar disintegration force.

[0203] The lubricants magnesium stearate (MgSt) and sodium stearyl fumarate (NaSF) were compared with glyceryl behenate, with varying amounts of lubricant used to achieve similar lubricating effects.

[0204] Due to the cohesive nature of Compound A, glidants were evaluated for high drug load formulations. Therefore, colloidal silicon dioxide (SiO2) was included in this study. Tablets in two experiments were coated with a film coat containing three globally accepted iron oxides.

[0205] [Table 3]

[0206] [Table 4]

[0207] N1 (Table 4) was initially considered the first choice and was therefore used as one repeat corner, and the repeat experiments were film-coated. N5, the opposite of N1, was used as the other repeat corner. Colloidal silicon dioxide was added to the repeat experiment. Finally, the high drug-loaded modified N1 formulation was roller-compacted (RC) to confirm the absence of any effect of using that manufacturing route.

[0208] The accelerated stability program used is shown below in Table 5. All conditions included pure drug substance as a reference.

[0209] [Table 5]

[0210] result The formulation in the tested tablets degrades at a significantly faster rate than the pure drug substance (i.e., Compound A) under all test conditions. Thus, while there is incompatibility between all excipients, some excipients accelerate degradation more than others. This is illustrated in Figure 2, where tablets stored at 50 / 75 for 45 days are compared with the pure drug substance stored under the same conditions and a standard solution freshly prepared from the same drug substance batch. Chromatograms are stacked (slightly shifted for clarity) in order of degradation.

[0211] Most of the degradation was observed in batch N7, which contained NaSF as a lubricant. Most of the degradation peaks were significantly larger than in the other batches, and one peak was absent in the other batches. This peak may be related to a specific incompatibility between NaSF and Compound A. N1 also decomposed slightly more than N4, but there was little difference between the drug substance and the freshly prepared standard in terms of stability.

[0212] Data from the batch stored for 21 days at 70 / 75 showed extreme levels of degradation, including secondary degradation; therefore, the data were not used to draw conclusions about the relative stability of the excipients. However, general trends from the other conditions were still evident. At 70 / XX, the degradation profile appeared significantly different from the other conditions. Without wishing to be bound by any particular theory, this is believed to be related to changes in the physical form of Compound A. Because the degradation profiles seen at 50 / XX and 70 / 75 were consistent with those at 50 / 75 and 60 / 40, it is believed that the drug substance was physically stable at these conditions, at least for the duration of the study. Based on this, the 70 / XX data was excluded from the shelf-life prediction model.

[0213] Tablet tensile strengths (TS) of over 2 megapascals (MPa) were achieved at compression pressures (CP) well below 150 MPa (Table 6). The normalized compression pressures (CP) for all batches were norm) are less than 100 MPa, which is excellent. Finally, the mass variations are all less than 1.5%, and most are less than 1% RSD. However, these values ​​will vary significantly with optimal formulation and processing, including roller compaction.

[0214] [Table 6]

[0215] Five different peaks were monitored under five different conditions; however, as noted above, the 70 / XX condition was excluded based on the high likelihood of conversion to Form B. Overall, Compound A in tablets containing glyceryl behenate appears to degrade slightly less than magnesium stearate.

[0216] MCC / DCPD may have a slight advantage in humid conditions, while MAN / MCC was advantageous in dry conditions. However, the differences were small, so the compression properties determined the final choice of filler.

[0217] In some conditions, L-HPC appeared to be less stable, and in others, NaCMC. Thus, NaSG appears to be optimal in terms of chemical compatibility.

[0218] N10 can be directly compared to N1 to assess the effect of the HPMC-based film coat on formulation stability. N11 can be directly compared to N5 to assess the effect of colloidal silicon dioxide. N12 was based on N1 but was roller-compacted and contained a drug loading of 25% instead of 1.25%. Therefore, the primary purpose of that batch was to confirm that the proposed manufacturing route was feasible for a high drug load formulation.

[0219] Multiple linear regression (MLR) decomposition monitoring Stability conditions were selected using an experimental design to determine degradation based on temperature, humidity, and selected excipients. Therefore, the data was evaluated using multiple linear regression (MLR). Because storage at 70 / XX for 45 days may have altered the form, this data was excluded. As with data from N10, N11, and N12, the above evaluation indicated that the changes from N1 and N5 were not insignificant.

[0220] The scaled and centered coefficients from the MLR model for the five degradation products are shown in Figure 3. In summary, GlyBeh appears to be better than MgSt, but the most important choice is to stay away from NaSF. Humidity is not a major issue, but increased temperature increases degradation.

[0221] Predicted shelf life Chemical incompatibility between excipients and Compound A was assessed using the modified Arrhenius equation shown in Equation 1. This approach uses the time to specification limit at different storage conditions to predict shelf life at other conditions (see Table 7).

number

[0222] The results shown in Table 7 were generated by excluding the 70 / XX data from the calculations. Additionally, models deemed unreliable were ignored from the results shown. For example, a reliable model could not be created for the RRT 0.91 peak. However, that degradation product was not the largest in any experiment and is therefore unlikely to limit shelf life. The information in Table 7 was further evaluated with MLR to understand the impact of each excipient on formulation shelf life. The model had an R of 0.96.2 and Q of 0.52 2 The coefficient plot is shown in Figure 4. This model supports the above results, which indicate that GlyBeh is a safer choice than MgSt in terms of the chemical stability of Compound A.

[0223] [Table 7]

[0224] The degradation peaks described herein can likely be assigned according to Table 8 below. The diastereoisomer AZ13703978 and the dimer AZ13785489 did not change significantly in the excipient compatibility studies and are therefore not discussed here.

[0225] [Table 8]

[0226] Tableting performance data was collected. The resulting model was very good, with regression coefficients (R 2 ) was 0.98 and the cross-correlation coefficient (Q2) was 0.90. The results show that MCC / DCPD was preferred over MAN / MCC, while L-HPC and NaSF performed the worst for disintegrant and lubricant, respectively.

[0227] Example 3 - Development of a quantitative formulation A Fractional Factorial Resolution III experimental design was established (Table 9) to evaluate the effect of a range of excipients and one critical process parameter on the performance of Compound A. The materials used in these experiments are listed in Table 10.

[0228] [Table 9]

[0229] [Table 10]

[0230] Drug burden The possible dose range for Compound A was 5 mg to 65 mg; therefore, the drug loading was selected to correspond to that range, converting to 1.25% to 16.25%. The amount of drug substance was not corrected for purity, except for a 1:1 (mol / mol) water content. A midpoint level of 8.75% was selected.

[0231] Binary filler level The primary filler, microcrystalline cellulose, was allowed to vary freely to account for all other variations in composition. The secondary filler, dibasic calcium phosphate dihydrate, was varied between 15% and 25%. These levels were chosen so that the yield pressure and strain rate sensitivity of each formulation were 110–160 MPa and 2%–25%, respectively. The maximum and minimum amounts of microcrystalline cellulose were 76% and 47%, respectively.

[0232] Amount of disintegrant The amount of disintegrant was based on the instructions for use of the pharmaceutical excipient; the usual concentration used in formulations is between 2% and 8%. Often, the concentration used is around 4%, but in many cases 2% is sufficient. Therefore, 2% was selected as the low level and 4% as the center point. Based on symmetry, 6% was used as the high level.

[0233] Amount of glidant Although the effect of glidants on dissolution was not evident in Example 2, there were indications of incompatibility between Compound A and colloidal silicon dioxide. For this reason, the lower level was set at 0%. In the compatibility study of Example 2, 0.25% SiO2 was used, so this level was chosen as the center point. In Example 2, colloidal silicon dioxide, Cab-O-Sil (Cabot Corp., Boston, MA, USA), was used, but in this experiment, silicon dioxide Syloid 244FP was chosen to improve handling. For symmetry reasons, the upper level of 0.5% was chosen.

[0234] Amount of lubricant In Example 2, it was found that 2% glyceryl behenate was insufficient to lubricate a direct compression formulation containing a 1.25% drug load. To ensure that the stability benefits seen with glyceryl behenate were not diminished when sufficient lubricant was used, additional experiments were conducted using 3% glyceryl behenate. 3% was selected as the low level of lubrication. Because the drug substance is very viscous, higher drug loads require more lubrication, so 5% was selected as the upper level, with 4% used as the center point.

[0235] Amount of film coating In the coating experiment of Example 3, 4.8 mg / cm 2 A total coating solids amount of 3%, corresponding to

[0236] Process parameter variations To understand how the formulation processes interact, the compaction force was varied. A suitable range for the Vector TFC-Labo roller compactor is 4 MPa to 8 MPa.

[0237] Evaluation of experimental design The experimental designs were evaluated using multiple linear regression (MLR) for the responses discussed below. Primarily, only linear coefficients were evaluated, but as explained above, fractional factorial designs can also evaluate interaction coefficients. Stability data were evaluated using reduced experimental designs.

[0238] scanning electron microscope Scanning electron microscope (SEM) images were collected for all steps from one of the center-point batches, namely N11. A Cressington 108 Autogold sputtering system coated the material with gold. Images were taken using an FEI Quanta 200 scanning electron microscope equipped with an Everhart Thornley (SE) detector.

[0239] Roll compression characterization Ribbon characterization The true density of representative secondary blends was determined in duplicate using an AccuPyc 1330. The envelope density of the ribbons was measured using a GeoPyc 1360 Envelope Density Analyzer. The analysis was performed in duplicate using the following settings: Sample size: approx. 2g Sample chamber diameter: 25.4mm Number of cycles: 7 Compaction force: 51N Conversion factor: 0.5153cm 3 / mm

[0240] The relative density of the ribbon, which is a good measure of the remaining compatibility of the material, was calculated by dividing the ribbon envelope density by the true density of a representative secondary blend.

[0241] Amount of fines A basic measurement of fines was determined by collecting ribbons from the roller compactor onto a 2 mm mesh. The ribbons were scattered onto a screen and everything that passed through the mesh was weighed and designated as fines. This was compared to the total amount of material exiting the roller compactor.

[0242] Granule characterization The bulk density of the secondary blend was compared to the bulk density of the final blend as a measure of the density increase brought about by the roller compaction process. Bulk density was determined according to USP.

[0243] Granule Size Distribution A Malvern Mastersizer 2000 (Malvern Instruments Ltd, Malvern, UK) laser diffraction analyzer was used for particle size distribution (PSD) measurements. Sample preparation was performed by gently adding 1 g of sample to the measurement tray before placing it in the dispersion unit. Three measurements were performed for each sample, and the Malvern software calculated the average d[0.1], d[0.2], d[0.5], d[0.8], and d[0.9]. Additionally, the span was calculated as a measure of the width of the size distribution.

[0244] Liquidity Determination transparency A Freeman Technology FT4 Powder Rheometer (Freeman Technology, Tewkesbury, UK) was used to measure the pressure drop across the powder bed. Measurements were performed at increasing normal stresses from 1 to 30 kPa and a constant airflow velocity of 2 mm / s. At each normal stress, the pressure drop was measured across the powder bed after the airflow velocity reached equilibrium at 2 mm / s. Scatter plots were generated to plot the pressure drop across the powder bed as a function of applied normal stress. Data analysis was performed using FT4 data analysis software.

[0245] wall friction angle Wall friction testing is performed using an FT4 Powder Rheometer by applying a wall-normal stress to the sample in a decreasing pattern. Before starting the measurement, a blade is used to condition the sample to remove localized stresses and excess air. A vented metal piston then applies pressure from above, compressing the powder bed. Finally, a metal piston equipped with a stainless steel plate with a 1.2 μm groove depth compresses the powder sample while rotating to measure frictional resistance. The load was varied from 1 kPa to 15 kPa. The roughness of the wall friction disc was Ra 1.2 μm. Angles of 30° or greater are considered sticky. Angles significantly smaller than 15° can result in insufficient grip during roller compaction, degraded compression properties during tableting, and potentially dissolution problems if associated with significant overlubrication.

[0246] mass flow rate Mass flow rates were measured with an Erweka GTB flow tester, which measures a predefined amount (g) of powder discharged from a hopper over a period of time (s) (Erweka GmbH, Heusenstamm, Germany). A 10 mm orifice was used. The test time was set to 10 s with a stirrer setting of 2. Typically, values ​​of 5 g / s or higher are required for proper die filling during tablet compression.

[0247] Formulation characterization Compression characteristics Compression properties were determined using an Erweka MultiCheck Turbo 3.

[0248] Elution Dissolution was determined for all batches initially and during stability storage according to Table 9.

[0249] Decomposition Assay and organic impurities were determined for all batches initially, while degradation was determined according to Table 9 during stability storage.

[0250] result Initially, the roller compactor was equipped with punch-type rolls with serrated surfaces, while the die-type rolls had smooth surfaces. Roller compaction did not work due to insufficient grip on the smooth rolls. Therefore, the smooth punch-type rolls were changed to ones with serrated surfaces, and the entire experimental plan was completed with that setup. The first two experiments were re-run, now designated N5 and N8.

[0251] Roller compaction characterization The roller compaction process was studied by determining the envelope density (ED) of each batch and then computing the relative density (RD) of the ribbons.

[0252] To understand the loading when scaling up the process, the bulk densities of the powder and granules (PDB and GBD, respectively) were determined. However, the density increase (DI) was also calculated as a measure of material densification during roller compaction unit operation. Batch N1 stands out as having very minimal densification, while N6 saw a 75% increase in bulk density. N11 is a clear outlier compared to the other two center points.

[0253] Finally, the amount of fines remaining after the roller compaction unit operation was determined. Although batch-to-batch fines differences are considered a relevant measure, overall fines levels from the small-scale unit used in this study are greater due to side seal wear.

[0254] Liquidity Determination The flow properties of the final blends were analyzed using three different methodologies (Table 11). Permeability is a measure of the cohesive properties of the final blend, while wall friction angle determines the stickiness of the blend. Finally, mass flow rate is a direct measure of the flow properties of the blend.

[0255] [Table 11]

[0256] Formulation characterization The most relevant physical tablet properties are shown in Table 12. CPnorm is an estimate of the compression pressure required to produce tablets with a tensile strength of 2.0 MPa. Mass variation is the relative standard deviation of the weights of 10 tablets. As is evident from the data in Table 12, the mass variation for all batches is less than 1.0%.

[0257] [Table 12]

[0258] Dissolution data for all batches are listed in Table 13. All batches reach 85% dissolution within 15 minutes, and for all batches except N1, all Compound A is released within 10 minutes.

[0259] [Table 13]

[0260] Six selected batches were stored for stability and analyzed for dissolution. Only N1 was affected by the various storage conditions after one month. See Tables 14, 15, and 16.

[0261] [Table 14]

[0262] [Table 15]

[0263] [Table 16]

[0264] Organic impurity data from one month of stability storage was also collected under various conditions. No significant differences were observed between storage at 5 / XX and 25 / 60, indicating that overall lower drug loading leads to increased degradation. Degradation was significant at both 40 / 75 and 50 / XX.

[0265] SEM images were captured for each step of the manufacturing process to better understand the impact of the processing route on the final formulation. Figure 5 shows the steps of the manufacturing process captured using SEM images. A selection of SEM images from each step of the manufacturing process is shown in Figure 6. Based on the results presented here and images of the material from the various steps, it was concluded that the milling and glidant blending steps offer little benefit to the quality of the formulation, but their elimination from the manufacturing route would improve the manufacturability aspect of the formulation when considering commercial formulation implementation.

[0266] The particle size distributions (PSD) of the final blends for all batches are shown in Figure 7. All distributions are trimodal. There is one hump below 10 μm, which is likely associated with the uncompacted API. The most prominent peak is above 100 μm, which is associated with the uncompacted material. The final peak is associated with the amount of granules in the final blend.

[0267] Dissolution was immediate for all tested batches except for N1, which still showed rapid dissolution. Drug release was largely unaffected during storage, except for batch N1, which showed a significant decrease in dissolution after 1 month of storage. However, approximately 85% dissolution was reached within 20 minutes at each condition.

[0268] Statistical evaluation All results were evaluated using multiple linear regression, attempting to establish a model for each response related to the factors in the experimental design. As noted above, batch N11 was an outlier compared to the other two centers, N9 and N10. To build relevant models, N11's results had to be excluded from all models. N1, the extreme corner with low levels of most factors, had to be excluded from the PSD model and related models, such as granule density. Finally, batch N4 had to be excluded from all models for the final formulation because tablets could not be produced from that batch.

[0269] Table 17 summarizes the most relevant models. The correlation coefficient R2 describes how well the data fit the model. The cross-correlation coefficient Q2 describes the model's predicted powder. The positive and negative columns list factors that are significant or nearly significant to the model in order of importance. For example, in the case of powder density, DCPD is the factor that most influences powder density increase. The amount of compound A has a negative effect on the model, which means that as the amount of compound A in the formulation increases, the bulk density of the powder decreases.

[0270] [Table 17]

[0271] Increasing the amount of disintegrant improved dissolution. The only batch that showed a slightly poor drug release profile was one batch with the lowest disintegrant level, so a higher amount of disintegrant should be sufficient. Increasing the amount of API also benefited overall dissolution, but increasing the lubricant had a negative effect on dissolution. Drug loading also decreased flowability but had a positive effect on dissolution.

[0272] With regard to formulation degradation, SiO2 resulted in increased degradation of some peaks, but as expected, reduced drug loading also increased overall degradation (see Figure 8).

[0273] Excipient Level Selection DCPD had a slight negative effect on some responses, but was necessary to control the strain rate sensitivity of the formulation, and therefore it was concluded that DCPD was maintained at a center-point level of 20%. While NaSG was beneficial for drug release, the center-point level was sufficient to ensure complete dissolution in 15 minutes. The lubricant glyceryl behenate had a negative effect on compaction properties and dissolution, but a positive effect on roller compaction.

[0274] The most influential excipient was silicon dioxide. In this study, hydrated silicon dioxide (Syloid 244FP) was used. Based on the results herein, SiO2 negatively impacts dissolution. However, SiO2 improved the flowability and compressibility properties of the formulation. The lowest drug loading suggests that no SiO2 should be included in the formulation, but as drug loading increases, the level of SiO2 also increases.

[0275] Example 4 - Lubricant Screen Different lubricants and amounts were studied. Three lubricants were tested: glyceryl behenate (GlyBeh), magnesium stearate (MgSt), and stearic acid (StAc). Tablets were manufactured by direct compression or using a dry granulation process. After analyzing the organic impurities of the directly compressed low-dose tablets, StAc was excluded from this study because the formulation exhibited a slightly worse degradation profile than the other two formulations.

[0276] Three different lubricants (GlyBeh, MgSt, and StAc) were investigated, and tablets of three different dosage strengths (5, 25, and 65 mg) were produced. The low-dose tablets were stored under three different conditions: 40°C / 75°C (closed), 50°C (open), and 50°C / 75°C (open). Next, two lubricants (GlyBeh and MgSt) were selected to produce two different dosage strengths (5 mg and 45 mg). Finally, tablets containing the final lubricant GlyBeh were produced in three different dosage strengths (4.8 mg, 24 mg, and 43 mg). The drug loading of the final formulation ranged from 1.3% to 11.4%, which corresponds to 1.2% to 10.7% considering purity. The stability of the tablets was studied and they were stored under five different conditions: -20°C, 25°C / 60°C, 30°C / 75°C, 40°C / 75°C, and 50°C.

[0277] The materials used in this study are provided in Table 19. [Table 18]

[0278] Equipment and Settings Tablets were manufactured using roller compaction (RC). However, in the first lubrication test, formulations were directly compressed, except for the 5 mg 1% IG GlyBeh formulation. All other batches were made using RC. The pharmaceutical unit operations used for formulations manufactured by RC were blending, co-milling, blending, roller compaction, milling, final blending, and compression; for tablets manufactured by direct compression, the manufacturing steps were blending, co-milling, final blending, and compression. Tablets during supportive stability testing were also film-coated. All equipment and settings are listed in Table 20.

[0279] [Table 19]

[0280] Blend I In the first blending step, the API, MCC, DCPD, NaSG, and SiO2 (if present) were mixed in a 2 L vessel at 30 rpm for 10 minutes.

[0281] Co-grinding The powder blend was milled to better disperse the silicon dioxide in the blend and ensure sufficient flow for subsequent unit operations. An 813 μm screen was used to ensure the primary particles remained intact, and a speed of 1500 rpm was used to keep the energy applied to the material low. No physical changes in the components were observed after the co-milling step.

[0282] Blend II In the second blending step, 50% of the total amount of lubricant was added (60% of the total amount of lubricant was added in the first lubrication test). A preblend was prepared by adding the lubricant to a small amount of Blend I through a 0.5 mm sieve. The preblend was mixed manually and added to Blend I, which was then blended at 30 rpm for 5 minutes (first lubrication test) or 10 minutes (second lubrication test and support stability). A sample (RC Blend) was removed for analysis.

[0283] Roller compaction and grinding The blend was then roller compacted according to the settings in Table 20. Ribbon samples were collected during the process. The ribbons and granules were weighed and crushed.

[0284] Final Blend The remaining 50% of the total amount of lubricant (40% for the first lubrication test) was added during the final blend. A preblend was prepared by adding the lubricant to a small amount of granules passed through a 0.5 mm sieve. The preblend was mixed by hand and added to the remaining granules, which were then blended at 30 rpm for 10 minutes. A sample of the final blend was removed for analysis.

[0285] compression Tablet weight was 400 mg for all batches. The first lubrication test was compressed on a Korsch EK0, while the other two tests were compressed on a Korsch XL-100. The compression profile was studied by compressing tablets from the second lubrication test at different compression forces (low, medium, and high). Tablet thickness and breaking force were measured at each compression force to establish a relationship between their IPC and compression force. The remaining material was compressed into tablets with a tensile strength of 2 MPa, which also applies to all materials from the first lubrication test and the support stability.

[0286] Film Coating Tablets from the supported stability study were coated with Ashland premix using a Vector LDCS according to the settings in Table 20. The premix was applied as a 10-15% solids suspension in purified water. The loading was approximately 4.8 mg / cm per tablet. 2 This corresponds to a weight increase of

[0287] Analysis and Response Flow function coefficients and wall friction angles The powder blends removed after Blend II were analyzed for flow function coefficient (ffc) and wall friction angle using a Schulze Ring Shear Tester. The settings used are shown in Table 21, and the test was performed once for the blends from the support stability test and twice for the other tests. The flow function coefficients were classified according to Jenike. Solids retention and flow as shown in Table 22.

[0288] [Table 20]

[0289] [Table 21]

[0290] powder density The true density of Blend II from the supporting stability study was analyzed using an AccuPyc 1330 with the following settings: 10 ml sample cell, 10 purges at 19.5 psi purge fill pressure, 10 runs at 19.5 psi run fill pressure, and an equilibration rate of 0.02 psi / min, except for the 4.8 mg formulation, which used 20 purges and 20 runs. Two replicate runs were performed.

[0291] Ribbon Density The envelope density of the ribbons was measured using a GeoPyc 1360 Envelope Density Analyzer. The analysis was performed in duplicate using the following settings: sample chamber diameter 25.4 mm, number of cycles 5, compaction force 51 N, and conversion factor 0.5153 cm 3 / mm.

[0292] Tablet characteristics Tablets from the second lubrication test and the support stability test were analyzed for weight, thickness, and breaking force using an Erweka Multicheck Turbo 3 tablet tester (n=10 for tablets from the second lubrication test and n=20 for tablets from the support stability test). The data generated was used to calculate weight variation (%RSD) and tablet tensile strength.

[0293] organic impurities Five-mg tablets (EB15-329701, EB15-329706, and EB15-329704) from the first lubrication test were studied for degradation products by UPLC gradient elution analysis of five tablets per sample dissolved in a diluent consisting of water:acetonitrile (50 / 50 (v / v)) supplemented with 0.03% TFA. Sample concentrations ranged from 0.1 to 0.5 mg / mL. The chromatography columns were 50 mm or 100 mm long, had an internal diameter of 2.1 mm, and were packed with Waters Acquity BEH C18 1.7 μm particles. The two mobile phase components were 0.03% TFA in water and 0.03% TFA in acetonitrile. A combination of linear gradient and isocratic elution was applied, with a total analysis time of 18 min. Impurity profiles of the samples were followed by UV detection at 227 nm.

[0294] Elution Tablets with 5 mg and 65 mg dosage strengths (EB15-329701, EB15-329706, EB15-329704, EB15-329703, and EB15-329707) from the first lubrication test were analyzed for dissolution. Dissolution tests were performed in HCl 0.1 M at 37° C. using USP Apparatus 2 at a rotation speed of 50 rpm using three tablets. Samples were removed at 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, and 120 minutes. At the end of the test, the rotation speed was increased to 200 rpm for infinity time points, and additional measurements were taken at 135 and 150 minutes. Further information on the settings used is provided in Table 23.

[0295] [Table 22]

[0296] Roller compaction of the 5 mg formulations (EB15-329701, EB15-329706, and EB15-329704) from the first lubrication study failed because the powder did not grip the roll and failed to form a sturdy ribbon. This indicated over-lubrication of the formulations, which the wall friction angles also indicated. Due to the roller compaction issues, all 5 mg formulations were directly compressed, and the resulting tablets were analyzed for stability degradation. Organic impurity results indicated that StAc was the worst choice in terms of degradation products, with GlyBeh having the best profile, followed closely by MgSt.

[0297] After analyzing the low-dose formulations for organic impurities, StAc was excluded from the study, and high-drug-load formulations (65 mg) were produced with GlyBeh and MgSt. Roller compaction of these batches performed quite well. While there were no issues with the MgSt-containing formulation, there were issues with the GlyBeh-containing formulation, where powder coated the rolls, indicating lack of lubrication (WFA = 28°). The RC process had to be stopped and the rolls cleaned during the process.

[0298] The dissolution profiles of all batches show that GlyBeh had the fastest dissolution profile, followed by MgSt and StAc.

[0299] The first 5 mg formulation was over-lubricated, so a new 5 mg formulation was produced without lubricant and glidant. Roller compaction of this formulation also failed, with squealing of the rolls, indicating insufficient lubrication. 1% intragranular GlyBeh was added, and roller compaction worked well (EB16-257401). However, the ribbons were too thin (relative density <0.5), and further experiments on the amount of lubricant and various process parameters of the roller compactor need to be investigated.

[0300] In a second lubrication study, GlyBeh and MgSt were used as lubricants to produce formulations with dosage strengths of 5 mg and 45 mg. Roller compaction of these batches proceeded smoothly, except for the 45 mg GlyBeh formulation. Powder formed a plug in the orifice to the roll, necessitating the RC process being stopped and the funnel and roll being cleaned. The RC process proceeded satisfactorily when the feeder screw speed was reduced from 24 rpm to 21 rpm and a small portion of the material was added. Data from tablet characterization indicated that tablets containing MgSt had lower tensile strength compared to tablets containing GlyBeh. Therefore, GlyBeh was selected as the final lubricant based on experience during the manufacturing process and the fact that GlyBeh has a superior dissolution profile and tablet tensile strength compared to MgSt.

[0301] support stability Disintegration, dissolution, and organic impurities after 3 months of storage were investigated. Disintegration analysis was performed using Erweka ZT32 (n=3, MilliQ water, 37℃, no disk).

[0302] result Ribbon and powder density The average ribbon density and powder density results are shown in Table 24.

[0303] [Table 23]

[0304] Flow function coefficients and wall friction angles The flow function coefficient and wall friction angle results for Blend II are shown in Table 25. According to the classification system by Jenike, all Blend IIs are classified as either easy-flowing (ffc 4-10) or free-flowing (ffc>10).

[0305] [Table 24]

[0306] Tablet characterization Tablet property results are summarized as averages in Table 26. Figure 9 shows plots of compression pressure and tensile strength for tablets from the second lubrication test.

[0307] The average tablet weight of tablets from the second lubrication test was high. The average tablet weight of the supported stability test was close to the nominal value, and the tablet weight variation (%RSD) was low (0.6-1.1%) for the 24 mg and 43 mg tablets, but high (3.6%) for the lower dose. Regarding compression of tablets from the supported stability test, all batches flowed fairly well but were sensitive to punch separation and fill depth adjustment.

[0308] [Table 25]

[0309] organic impurities The degradation product profiles of 5 mg tablets (EB15-329701, EB15-329706, and EB15-329704) containing three different lubricants, GlyBeh, StAc, and MgSt, from the initial lubrication study were analyzed after storage at 40°C / 75°C (closed), 50°C (open), and 50°C / 75°C (open) for one month. Tablets using GlyBeh as the lubricant were also analyzed for organic impurities after three months of storage in the above environments.

[0310] The organic impurities at time zero were 0.7% in all three 5 mg tablet types, corresponding to the impurity profile of the API. Therefore, the manufacturing process of the formulation does not increase degradation products.

[0311] Storage at 40°C / 75% RH (closed) for 1 month resulted in total organic impurities of 0.9% (GlyBeh), 1.0% (StAc), and 1.1% (MgSt). After subtracting the contribution from the API, the increase in organic impurity levels was 0.2% (GlyBeh), 0.3% (StAc), and 0.4% (MgSt).

[0312] Storage at 50°C (open) for one month resulted in total organic impurities of 2.8% (GlyBeh), 6.7% (StAc), and 3.0% (MgSt). Subtracting the contribution from the API, the increase in organic impurity levels was 2.1% (GlyBeh), 6.0% (StAc), and 2.3% (MgSt). The increase in impurities primarily involved peaks close to the peak of Compound A. The impurity AZ13701214 increased by approximately 0.1% in all three tablet types, while the two diastereoisomers eluting at 7.7 minutes increased significantly in the StAc tablet.

[0313] Storage at 50°C / 75% RH (open) for one month resulted in total organic impurity levels of 4.8% (GlyBeh), 5.0% (StAc), and 4.5% (MgSt). After subtracting contributions from the material, the increase in organic impurity levels was 4.1% (GlyBeh), 4.3% (StAc), and 3.8% (MgSt). The synthetic impurity AZ13701214 increased, as did a peak close to the Compound A peak, and a later-eluting impurity at 12 minutes.

[0314] The organic impurity results after one month of storage at three different conditions revealed that the formulation with StAc as lubricant had a slightly worse degradation profile compared to the other two formulations.

[0315] Degradation products of 5 mg tablets (EB15-329701) containing GlyBe as a lubricant were also analyzed after storage at 40°C / 75%RH (closed), 50°C (open), and 50°C / 75%RH (closed) for 3 months. After 3 months at 40°C / 75%RH (density), the total amount of impurities increased from 0.7 area% at time zero to 1.4 area% (0.7 area% at time zero, 0.9 area% at 1 month, and 1.4 area% at 3 months). After 3 months, AZ13701214, with an RRT of 0.79, increased from 0.3 area% to 0.5 area%. One of the formamide / diastereoisomers, AZ13785488, with an RRT of 1.31, increased slightly from 0.2 area% to 0.3 area% under the same conditions.

[0316] After 3 months of storage at 50°C (open), total impurities increased from 0.7 area% at time zero to 4.4 area% (0.7 area% at time zero, 2.8 area% at 1 month, and 4.4 area% at 3 months). The increase was primarily due to impurities eluting after the main Compound A peak. The impurity at RRT 1.05 increased from <0.05 area% at time zero to 1.0 area% after 3 months. The formamide diastereoisomers AZ13785488 and AZ13910537 at RRT 1.30 and RRT 1.31 increased from 0.2 area% to 0.7 area% and 0.8 area%, respectively.

[0317] After 3 months of storage at 50°C / 75% RH (open), total impurities increased from 0.7 area% at time zero to 9.9 area% (0.7 area% at time zero - 4.8 area% at 1 month - 9.9 area% at 3 months). Under these conditions, an increase in impurities eluting both before and after the main Compound A peak was observed. For example, the impurity AZ13701214 at an RRT of 0.79 increased from 0.3 area% at time zero to 2.5 area% after 3 months. Other impurities eluting at RRTs of 0.9 and 1.1 increased from <0.05 area% at time zero to approximately 1.4 area% after 3 months of storage.

[0318] The synthetic by-product AZ13905472, which has low UV absorption at 227 nm and elutes at an RRT of 0.76, just before AZ13701214, was shown to be unaffected by different tablet compositions and storage conditions.

[0319] The total amount of organic impurities increased by 0.5 area % after 3 months of sealed storage at 40°C / 75% RH. After 3 months of open storage at 50°C, the total amount of impurities increased by 3.7 area % and at 50°C / 75% RH, the total amount of impurities increased by 9.2 area %.

[0320] Elution First lubrication test The dissolution profiles of tablets from the first lubrication study are shown in Figures 10 and 11. Figure 10 shows results from 5 mg tablets (EB15-329701, EB15-329706, and EB15-329704) at initial conditions and after one month of storage at 40°C / 75°C. Figure 11 shows results for 65 mg tablets (EB15-329703 and EB15-329707) at initial conditions. Dissolution was rapid for both dosage strengths, with 80% dissolved within 10 minutes.

[0321] Support stability - organic impurities The results of the analysis of organic impurities for tablets stored at -20°C, 25°C / 60, 40°C / 75 and 50°C for 1 month and 3 months are shown in Tables 27, 28 and 29 for 4.8 mg, 24 mg and 43 mg tablets, respectively. All detectable peaks were within specification.

[0322] [Table 26]

[0323] [Table 27]

[0324] [Table 28]

[0325] Elution Table 30 shows dissolution results for all dosage strengths, initially and after 3 months of storage at -20°C, 25°C / 60°C, 40°C / 75°C, and 50°C. Results are presented as the average of three measurements (six for initial conditions), and values ​​reported are the 15-minute reading. Dissolution was rapid for all dosage strengths under all conditions, with nearly 100% dissolution at 15 minutes for all batches.

[0326] [Table 29]

[0327] Collapse Table 31 shows the disintegration time results for coated tablets stored for 3 months under five different conditions for a maximum of three tablets. Disintegration times were rapid for all batches (within 4 minutes and 10 seconds), and this time increased with increasing drug load and temperature / humidity.

[0328] [Table 30]

[0329] A non-functional aesthetic hypromellose-based film coat is used as the coating agent. The amount of film coat is varied based on the surface area of ​​the tablet to ensure good coating coverage regardless of tablet size. The formulation is coated with approximately 4.8 mg / cm. 2 of film coat was applied, which corresponds to 3% of the 400 mg tablet cores (10 mm regular concave round used here) and 3.3% of the 300 mg tablet cores (9 mm regular concave round).

[0330] The compositions of the three manufactured supporting stability batches are shown in Table 32.

[0331] [Table 31]

[0332] Example 5 - Exemplary Compositions For a 400 mg tablet, a dosage form containing 45 mg of Compound A would have a drug load of 11.25% for the 400 mg tablet, compared to 5 mg of Compound A (1.25% drug load for the 400 mg tablet). Because the lowest possible dose was 5 mg, a drug load of 1.25% would be required for the same 400 mg core weight. The formulation contains Compound A as the drug substance, microcrystalline cellulose and dibasic calcium phosphate dihydrate as diluents, sodium starch glycolate as a disintegrant, silicon dioxide as a glidant, and glyceryl behenate as a lubricant. Glyceryl behenate is added both intragranularly and extragranularly. To provide size-matched formulations for clinical studies, the silicon dioxide and glyceryl behenate are varied depending on the drug load to balance the formulation's cohesive and adhesive properties while maintaining good formulation stability. The amount of microcrystalline cellulose is also varied to obtain the target formulation weight and correct for the purity of the drug substance. The amounts of each component are calculated according to Table 33. The composition of the tablet core is shown in Table 34.

[0333] [Table 32]

[0334] [Table 33]

[0335] Exemplary compositions, for example, 10 mg, 25 mg, and 40 mg compositions of Compound A, are provided in Figure 12 and Tables 35, 36, 38, and 39 and 36 below.

[0336] [Table 34]

[0337] [Table 35]

[0338] [Table 36]

[0339] [Table 37]

[0340] * * * * * * * All documents, patents, patent applications, publications, product descriptions, and protocols cited throughout this application are hereby incorporated by reference in their entirety for all purposes.

[0341] The embodiments illustrated and described herein are intended solely to teach those skilled in the art the best way known to the inventors to make and use the invention. As will be appreciated by those skilled in the art in light of the above teachings, modifications and variations of the above-described embodiments of the invention are possible without departing from the invention. It is therefore understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

[0342] The present application also includes the following aspects. [Aspect 1] (a) Formula (I): [ka] [In the formula, R 1 teeth, [ka] and; R 2 are hydrogen, F, Cl, Br, OSOC 1-3 Alkyl or C 1-3 is alkyl; R 3 are hydrogen, F, Cl, Br, CN, CF3, SO2C 1-3 Alkyl, CONH2 or SO2NR 4 R 5 where R4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or R 6 may be substituted by 1, 2 or 3 F and / or OH, OC 1-3 Alkyl, N(C 1-3 alkyl), optionally substituted by cyclopropyl or tetrahydropyran; C 1-3 is alkyl; R 7 is hydrogen, F, Cl or CH3; X is O, S or CF2; Y is O or S; Q is CH or N. or a pharmaceutically acceptable salt thereof; (b) about 55 to about 75 wt % pharmaceutical diluent; (c) compression aid, about 15% to about 25%; about 3.0% to about 5.0 wt% of a pharmaceutical disintegrant; (d) about 0.00 to about 1.0 wt % of a pharmaceutical glidant; and (e) about 2 to about 6 wt % pharmaceutical lubricant; (wherein the weights of the ingredients add up to 100). [Aspect 2] 2. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical lubricant is glycerol behenate. [Aspect 3] 3. The pharmaceutical composition of embodiment 1 or 2, wherein the pharmaceutical diluent is microcrystalline cellulose. [Aspect 4] Aspect 4. The pharmaceutical composition of any one of Aspects 1 to 3, wherein the compression aid is dibasic calcium phosphate dihydrate. [Aspect 5] Aspect 5. The pharmaceutical composition according to any one of aspects 1 to 4, wherein the pharmaceutical disintegrant is sodium starch glycolate. [Aspect 6] Aspect 6. The pharmaceutical composition of any one of aspects 1-5, wherein the pharmaceutical flow enhancer is silicon dioxide. [Aspect 7] 7. The pharmaceutical composition according to any one of aspects 1 to 6, in the form of a tablet. [Aspect 8] 8. The pharmaceutical composition of embodiment 7, further comprising a tablet core. [Aspect 9] 9. The pharmaceutical composition of any one of Aspects 1 to 8, wherein the compound of Formula (I) is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (Compound A). [Aspect 10] 10. The pharmaceutical composition of embodiment 9, wherein compound A is present in an amount of about 3 to about 10 wt %. [Aspect 11] 11. The pharmaceutical composition of embodiment 10, wherein the pharmaceutical lubricant is glycerol behenate, and the glycerol behenate is present at about 2.5 to about 4.5 wt %. [Aspect 12] 12. The pharmaceutical composition of embodiment 10 or 11, wherein the pharmaceutical flow enhancer is silicon dioxide, and the silicon dioxide is present at about 0.05 to about 0.25 wt %. [Aspect 13] 13. The pharmaceutical composition of any one of aspects 10 to 12, wherein the pharmaceutical disintegrant is sodium starch glycolate, and the sodium starch glycolate is present in an amount of about 3.5 to about 4.5 wt %. [Aspect 14] 14. The pharmaceutical composition of any one of aspects 10 to 13, wherein the compression aid is dibasic calcium phosphate dihydrate, and the dibasic calcium phosphate dihydrate is present in an amount of about 18 to about 22 wt %. [Aspect 15] 15. The pharmaceutical composition according to any one of aspects 10 to 14, wherein the diluent is microcrystalline cellulose, and the microcrystalline cellulose is present in an amount of about 55 to about 70 wt %. [Aspect 16] 16. The pharmaceutical composition of any one of aspects 1 to 15, wherein the compound of formula (I) is Compound A free base. [Aspect 17] 16. The pharmaceutical composition according to any one of aspects 1 to 15, wherein the compound of formula (I) is a pharmaceutically acceptable salt of Compound A. [Aspect 18] 18. The pharmaceutical composition of any one of Aspects 1 to 17, wherein the compound of Formula (I) is present in the composition in an amount of from about 5 mg to about 50 mg. [Aspect 19] 18. The pharmaceutical composition of any one of Aspects 1 to 17, wherein the compound of Formula (I) is present in the composition in an amount of from about 10 mg to about 40 mg. [Aspect 20] 18. The pharmaceutical composition according to any one of aspects 1 to 17, wherein the compound of formula (I) is present in the composition in an amount of 10 mg. [Aspect 21] 18. The pharmaceutical composition of any one of aspects 1 to 17, wherein the compound of formula (I) is present in the composition in an amount of 25 mg. [Aspect 22] 18. The pharmaceutical composition according to any one of aspects 1 to 17, wherein the compound of formula (I) is present in the composition in an amount of 40 mg. [Aspect 23] 23. A method of treating an obstructive airway disease in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition according to any one of aspects 1 to 22. [Aspect 24] 24. The method of embodiment 23, wherein the obstructive airway disease is bronchiectasis. [Aspect 25] 24. The method of embodiment 23, wherein the obstructive airway disease is chronic obstructive pulmonary disease (COPD). [Aspect 26] 24. The method of embodiment 23, wherein the obstructive airway disease is asthma. [Aspect 27] 27. The method of embodiment 26, wherein the asthma is bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, or dust asthma. [Aspect 28] 23. A method of treating cystic fibrosis in a patient in need thereof, comprising administering to said patient a pharmaceutical composition according to any one of aspects 1 to 22. [Aspect 29] 23. A method of treating anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition according to any one of aspects 1 to 22. [Aspect 30] 30. The method of embodiment 29, wherein treating comprises decreasing the patient's anti-neutrophil cytoplasmic autoantibody (ANCA) blood levels compared to the patient's ANCA blood levels before treatment. [Aspect 31] The method of embodiment 30, wherein the reduction in ANCA blood levels in the patient is at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. [Aspect 32] The method of embodiment 30 or 31, wherein the ANCA blood level is measured in the patient's plasma, serum, or a combination thereof. [Aspect 33] 33. The method of any one of aspects 30 to 32, wherein the ANCA concentration is a PR3 ANCA concentration. [Aspect 34] 33. The method of any one of aspects 30 to 32, wherein the ANCA concentration is a myeloperoxidase (MPO) ANCA concentration. [Aspect 35] The method of any one of aspects 29 to 34, wherein the ANCA-associated vasculitis is granulomatosis with polyangiitis (GPA). [Aspect 36] The method of any one of aspects 29 to 34, wherein the ANCA-associated vasculitis is microscopic polyangiitis (MPA). [Aspect 37] 36. The method of embodiment 35, wherein the patient has a Wegener's Granulomatosis-specific Birmingham Vasculitis Activity Score (BVAS / WG)>0 at the start of treatment, and wherein the treatment comprises decreasing the patient's BVAS / WG score, compared to the patient's BVAS / WG score before treatment. [Aspect 38] The method of embodiment 35, wherein the patient is in GPA remission at the start of treatment. [Aspect 39] The method of embodiment 38, wherein remission is defined as a BVAS / WG score of 0. [Aspect 40] The method of embodiment 38 or 39, wherein treating comprises maintaining GPA remission in the patient during or after treatment. [Aspect 41] The method of embodiment 37, wherein treating comprises reducing the patient's BVAS / WG score by 1 point or more. [Aspect 42] The method of embodiment 37, wherein treating comprises reducing the patient's BVAS / WG score to 0. [Aspect 43] The method of embodiment 37, wherein treating comprises inhibiting GPA flare, where flare is defined as an increase in BVAS / WG of 1 or more points. [Aspect 44] The method of any one of aspects 38 to 43, wherein the patient has been treated with rituximab, cyclophosphamide, steroids, or a combination thereof prior to administration of the pharmaceutical composition. [Aspect 45] The method of embodiment 44, wherein the patient is being treated with a steroid prior to administration of the pharmaceutical composition. [Aspect 46] The method of embodiment 45, wherein the steroid is a corticosteroid. [Aspect 47] The method of embodiment 46, wherein the corticosteroid is a glucocorticoid. [Aspect 48] 45. The method of embodiment 44, wherein the patient is being treated with rituximab prior to administration of the pharmaceutical composition. [Aspect 49] The method of any one of embodiments 29-48, wherein treating comprises improving the patient's Short Form Health Survey questionnaire (SF-36) score compared to the patient's SF-36 score before treatment. [Aspect 50] The method of any one of aspects 29 to 49, wherein treating comprises reducing the number of CD19+ B cells in the patient compared to the number of CD19+ B cells in the patient before treatment. [Aspect 51] The method of any one of aspects 29-50, wherein the method comprises improving the patient's Vasculitis Damage Index (VDI) compared to the VDI before treatment. [Aspect 52] The method of any one of aspects 29 to 51, further comprising administering to a patient in need thereof one or more additional active agents. [Aspect 53] 53. The method of embodiment 52, wherein the one or more additional active agents comprises an anti-CD20 monoclonal antibody. [Aspect 54] 54. The method of embodiment 53, wherein the anti-CD20 monoclonal antibody is rituximab. [Aspect 55] The method of any one of embodiments 52-54, wherein the one or more additional active agents comprises an anti-TNFα monoclonal antibody. [Aspect 56] 56. The method of embodiment 55, wherein the anti-TNFα monoclonal antibody is infliximab. [Aspect 57] 57. The method of any one of embodiments 52-56, wherein the one or more additional active agents comprises cyclophosphamide (CYC). [Aspect 58] The method of any one of embodiments 52-57, wherein the one or more additional active agents comprises a steroid.

Claims

[Claim 1] The invention described in the specification or drawings of this application.

Images