Formulation of pan-JAK inhibitors

Abstract

The present disclosure relates to formulations comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and methods of preparation.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 597,934, filed November 10, 2023, U.S. Provisional Application No. 63 / 501,086, filed May 9, 2023, and U.S. Provisional Application No. 63 / 385,847, filed December 2, 2022, the contents of each of which are incorporated by reference in their entirety. [Background technology]

[0002] WO2011 / 051452 discloses compounds useful as Janus kinase inhibitors (including JAK1 inhibitors, JAK2 inhibitors, JAK3 inhibitors, and TYK2 inhibitors). The compounds disclosed therein have utility in the treatment of a variety of diseases, including respiratory conditions such as asthma and COPD, as well as other inflammatory processes that may be associated with eosinophilic or non-eosinophilic inflammation. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2011 / 051452 Summary of the Invention [Problem to be solved by the invention]

[0004] Medications for the treatment of respiratory disorders are often administered by dry powder inhalation devices. Preparing respiratory medications as dry powders containing inhalation excipients such as lactose is complex and unpredictable. There is a continuing need for stable dry powder formulations that exhibit desirable bioavailability and physical properties. Physical properties are important for efficient handling and processing of the drug substance, ensuring that an effective dose is delivered to the correct part of the lung, and that the drug is effective in treating respiratory disorders. Various formulation techniques are known in the art and can be applied to drug compounds to produce inhalation powders with desired drug delivery properties. [Means for solving the problem]

[0005] Disclosed herein are methods and formulations of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile, having the structure shown below, and referred to herein as Compound I.

[0006] [ka] Compound I is also referred to as (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile.

[0007] As noted above, there is a continuing need to treat inflammatory processes associated with asthma and COPD, as well as eosinophilic or non-eosinophilic inflammation, in combination with the potent JAK inhibitory activity of Compound I, demonstrating the need for chemically stable formulations of Compound I suitable for commercial use. The formulations of Compound I disclosed herein meet this and other needs.

[0008] The present disclosure relates to novel formulations and methods used to prepare the novel formulations. [ka] or a pharmaceutically acceptable salt, solvate, clathrate, or co-crystal thereof, as well as formulations and methods comprising lactose and magnesium stearate.

[0009] In particular, the present disclosure relates to, inter alia, the following compound I [ka] or a pharmaceutically acceptable salt thereof, lactose, and magnesium stearate. The formulation is useful for treating asthma and COPD. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 shows the sampling plan used to measure drug content and content uniformity. [Figure 2] FIG. 1 shows delivery efficiency data (delivered dose) for 2 mg formulations containing Compound I. [Figure 3] FIG. 1 shows delivery efficiency data (delivered dose) for 4 mg formulations containing Compound I. [Figure 4] FIG. 1 shows the design of a phase 1 clinical trial of a formulation containing Compound I. [Figure 5] FIG. 1 shows a survey of FeNO changes from day 1 to day 17 in patients administered formulations containing Compound I (0.6 mg QD, 2.0 mg QD, 4.0 mg BID, and 8.0 mg BID). The patients were characterized by mild asthma and were not receiving inhaled corticosteroid (ICS) therapy. [Figure 6] This figure shows the percentage of patients who achieved a predefined baseline FeNO reduction rate at any time point from pre-dose on Day 1 to the final day of dosing (Day 10). The patients had mild asthma and were not receiving inhaled corticosteroid (ICS) therapy. [Figure 7a]This figure shows a survey of FeNO changes from day 1 to day 17 in patients administered a formulation containing Compound I (4.0 mg BID). The patients were characterized by moderate to severe asthma and were using ICS / LABA basal therapy. [Figure 7b] This figure shows a survey of FeNO changes from day 1 to day 17 in patients administered a formulation containing Compound I (4.0 mg BID). The patients were characterized by moderate to severe asthma and were using ICS / LABA basal therapy. [Figure 8] FIG. 1 compares the reduction in FeNO in Th2-rich patients with moderate to severe asthma administered a formulation containing Compound I (4.0 mg BID) or a formulation containing TD-8236 (1.5 mg QD). [Figure 9] This figure shows the placebo-corrected mean FeNO change rate from before administration on Day 1 to the final day of administration (Day 10) for the ITT and PP patient populations administered a formulation containing Compound I (4.0 mg BID). The patients had moderate to severe asthma and were using ICS / LABA basal therapy. [Figure 10] This figure shows the placebo-corrected mean FeNO change rate from before administration on Day 1 to the final day of administration (Day 10) (blood eosinophil subgroup). The patients had moderate to severe asthma and were using ICS / LABA basal therapy. [Figure 11] This figure shows the percentage of patients who achieved a predefined baseline FeNO reduction rate at any time point from before administration on Day 1 to the final day of administration (Day 10). The patients had moderate to severe asthma and were using ICS / LABA basal therapy. DETAILED DESCRIPTION OF THE INVENTION

[0011] As used herein, (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I) [ka] Disclosed are formulations and methods for making the same, comprising: In some embodiments, the formulation comprises about 0.5-11% by weight of Compound I, about 87.0-99.0% by weight of lactose, and about 0.5-2.0% by weight of magnesium stearate.

[0012] The formulations and preparation methods disclosed herein exceed expectations in that they result in mixtures of Compound I, magnesium stearate, and lactose with sufficient drug content and uniformity (content uniformity). This discovery led to clinical trials of formulations containing Compound I, lactose, and magnesium stearate. Prior to this discovery, the lack of uniformity and low drug content in existing formulations of Compound I prevented clinical trials of Compound I.

[0013] Also provided herein are methods of treating respiratory diseases (e.g., COPD and asthma) using formulations comprising Compound (I), lactose, and magnesium stearate. Such methods of treatment unexpectedly demonstrate clinically significant benefits against eosinophilic inflammation in asthma patients.

[0014] A further unexpected discovery is that a formulation containing Compound (I), lactose, and magnesium stearate results in clinically meaningful reductions in FeNO at low doses delivered by a single capsule. In contrast, other JAK inhibitors require higher API doses, which are achieved by administering multiple capsules. Therefore, the present specification also provides a method for reducing exhaled nitric oxide (FeNO) levels using a formulation containing Compound (I), lactose, and magnesium stearate.

[0015] definition It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Preferred materials and methods are described herein; however, other methods and materials similar or equivalent to those described herein can be used in the practice of this disclosure.

[0017] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a combination of two or more such excipients, reference to "a glidant" includes one or more glidants or mixtures of glidants, reference to "a filler" includes one or more fillers or mixtures of fillers, etc. As used herein, the term "or" should be understood to be inclusive and encompasses both "or" and "and," unless specifically stated otherwise or apparent from the context.

[0018] As used herein, the term "about" should be understood to mean within normal tolerances in the art (e.g., within two standard deviations of the mean) unless specifically stated otherwise or clear from the context. "About" can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value.

[0019] As used herein, the term "comprising" and variations thereof are intended to be non-limiting, such that the listing of items does not exclude other similar items that may be useful in the materials, compositions, devices, and methods of the present technology. Similarly, the terms "can" and "may," and variations thereof, are intended to be non-limiting, such that a statement that an embodiment can or may include a particular element or feature does not exclude other embodiments of the present technology that do not include such element or feature. While the non-limiting term "comprising" (synonyms of terms such as including, containing, or having) is used herein to describe and claim the present disclosure, technology, or embodiments thereof, more restrictive terminology such as "consisting of" or "consisting essentially of" the listed components may instead be used to describe the present disclosure, technology, or embodiments thereof.

[0020] As used herein, the term "substantially" is understood to be within a narrow range of variation in the art, or otherwise within normal acceptance in the art, unless specifically stated or clear from the context. "Substantially" can be understood as within 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.001% of the specified value.

[0021] A "subject" or "patient" refers to any animal, such as a mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc.

[0022] A "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response, including an amount of a compound sufficient to effect treatment of a disease when administered to a subject for treating such disease. The effective amount varies depending on the compound, the disease and its severity, and the age, weight, etc., of the patient being treated. An effective amount can encompass a range of amounts. As understood in the art, an effective amount can be one or more doses. That is, a single administration or multiple administrations may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in relation to the administration of one or more therapeutic agents; if a single agent, in combination with one or more other agents, can achieve or achieve a desired or effective result, that administration can be considered an effective amount. The appropriate dose of any co-administered compound can optionally be reduced due to the combined effects (such as additive or synergistic effects) of the compounds.

[0023] As used herein, the terms "treat," "treatment," and "treating" are defined as the application or administration of a therapeutic agent or formulation to a subject, or to a tissue or cell line isolated from a subject with a respiratory disease (e.g., for diagnostic or ex vivo uses). Such treatments can be specifically tailored or modified based on knowledge gained from the field of pharmacogenomics.

[0024] As used herein, the terms "formulation," "pharmaceutical formulation," and "dry powder pharmaceutical formulation" refer to a mixture, aggregate, solution, or other combination of materials that includes an active pharmaceutical ingredient (API). In a non-limiting example, a formulation includes an API and one or more excipients.

[0025] As used herein, the terms "mixing" or "mixed" are used to refer to the act of adding two or more ingredients together to prepare a mixture or premix. This definition means that two or more ingredients were not previously in contact with each other, but by mixing, the ingredients are brought into contact with each other. Examples of ingredients that may be mixed include, but are not limited to, lactose, magnesium stearate, an API, an excipient premix (i.e., a mixture of lactose and MgSt), and an API premix (i.e., a mixture of API and MgSt).

[0026] As used herein, the terms "processing" or "processed" are used to refer to particle size reduction and formulation methods, including, but not limited to, blending, high shear mixing, milling, mechanofusion, mixing, and micronization methods. Examples of processing methods are described herein. In one embodiment, processing includes any significant handling of the premix or formulation. In one embodiment, significant handling of the premix or formulation includes mixing the premix or formulation.

[0027] As used herein, the terms "resting," "rested," and "resting period" are used to refer to a formulation method in which the formulation is in a waiting state and therefore is not subjected to any further movement, processing, or any formulation procedure, such as agitating the formulation, for a predetermined period of time. It should be recognized that the purpose of the resting period is to dissipate residual energy within the formulation. In some embodiments, the residual energy within the formulation is a static charge.

[0028] As used herein, the terms "co-milling" or "co-milled" are used to refer to various powder processing methods used to break up agglomerates. Such methods include, but are not limited to, screen mills, which may be of various shapes, such as conical. In one embodiment, co-milling refers to screen milling.

[0029] As used herein, the terms "mixing," "mixing," and "mixed" refer to mixing multiple components to obtain a formulation. The resulting mixed formulation may be homogeneous. Also as used herein, the term "mixture" is used to describe the product obtained from mixing. In such a context, "mixture" is synonymous with "formulation."

[0030] As used herein, the term "high shear mixing" refers to combining or mixing multiple ingredients to obtain a formulation, such a process being carried out with a total energy input of 200-500 kJ / kg. Examples of high shear mixing processes include, but are not limited to, turbo high speed variable (TRV) mixing.

[0031] As used herein, the term "content uniformity" refers to the uniformity of the active pharmaceutical ingredient distributed throughout a mixture. Content uniformity is expressed as the relative standard deviation (RSD) of the mean of the sample analyses.

[0032] As used herein, the terms "mass median aerodynamic diameter" and "MMAD" refer to the aerodynamic diameter at which half of the aerosol particle mass is occupied by particles having an aerodynamic diameter greater than the median and half is occupied by particles having an aerodynamic diameter less than the median. As used herein, the terms "MMAD" and "diameter" are used interchangeably.

[0033] As used herein, the term "fine particle mass" or "FPM" is used to refer to the mass of a metered dose composed of drug particles having an aerodynamic particle diameter of 5 μm or less.

[0034] As used herein, the term "fine particle fraction" or "FPF" refers to the mass of fine particles expressed as a percentage of the total amount of drug recovered from the cascade impactor (i.e., the total amount of drug recovered from the induction port into the micro-orifice collector (MOC)).

[0035] As used herein, the term "target dose" refers to the amount of active pharmaceutical ingredient present in a single unit dose (e.g., the amount present in a single capsule or the amount present in a single blister). In some embodiments, the target dose is about 0.1-0.5 mg of Compound I. In some embodiments, the target dose is about 1.0-3.0 mg of Compound I. In some embodiments, the target dose is about 3.0-5.0 mg of Compound I. In some embodiments, the target dose is about 0.2 mg of Compound I. In some embodiments, the target dose is about 2.0 mg of Compound I. In some embodiments, the target dose is about 4.0 mg of Compound I.

[0036] As used herein, the term "delivered dose" refers to the amount of active pharmaceutical ingredient delivered to a subject with each actuation of a delivery device. The delivered dose is expressed as a percentage of the target dose of Compound I.

[0037] The present disclosure also encompasses salt forms of the compounds described herein. Examples of salts (or salt forms) include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is incorporated herein by reference in its entirety.

[0038] As used herein, the term "mild asthma" refers to asthma that is well controlled with reliever medication alone as needed, or with low-intensity controller therapy such as low-dose inhaled corticosteroids, leukotriene receptor antagonists, or chromones.

[0039] As used herein, the term "moderate asthma" refers to asthma that is well controlled with low-to-moderate doses of inhaled corticosteroids, with or without long-acting beta-agonist therapy (LABA) or other adjunctive controller therapy.

[0040] As used herein, the term "moderate to severe asthma" refers to asthma that requires moderate to high doses of inhaled corticosteroids, with or without long-acting beta-agonists or other adjunctive therapies, to prevent it from becoming uncontrolled, or asthma that remains uncontrolled despite such treatment.

[0041] It will be appreciated that the term "asthma" is used to refer to either "mild asthma," "moderate asthma," or "moderate to severe asthma."

[0042] As used herein, the term "ICS naive" is used to refer to patients who have never been treated with an inhaled corticosteroid.

[0043] As used herein, "AUC 0~∞ The term "AUC" refers to the total area under the plasma concentration-time curve extrapolated to infinity. 0~∞ Values ​​are reported in units of h·pg / mL or h·picograms / milliliter.

[0044] As used herein, "AUC 0~最終非ゼロ The term "AUC" refers to the total area under the plasma concentration-time curve from dosing (time 0) to the time of the last measurable (non-zero) concentration. 0-最終非ゼロ Values ​​are reported in units of h·pg / mL or h·picograms / milliliter.

[0045] As used herein, "AUC 投与間隔 The term "AUC" refers to the total area under the plasma concentration-time curve over a 10-day dosing interval. 投与間隔Values ​​are reported in units of h·pg / mL or h·picograms / milliliter.

[0046] As used herein, "AUC 0~12時間 The term "AUC" refers to the total area under the plasma concentration-time curve from dosing (0 hours) to 12 hours after dosing (12 hours). 0~12時間 Values ​​are reported in units of h·pg / mL or h·picograms / milliliter.

[0047] As used herein, "AUC 0~24時間 The term "AUC" refers to the total area under the plasma concentration-time curve from dosing (time 0) to 24 hours after dosing (time 24). 0~24時間 Values ​​are reported in units of h·pg / mL or h·picograms / milliliter.

[0048] As used herein, "C トラフ The term " refers to the trough concentration of Compound I in plasma before administration of a subsequent dose. トラフ Values ​​are reported in units of pg / mL or picograms per milliliter.

[0049] As used herein, "C 最大 The term "C" refers to the maximum concentration of Compound I in plasma before administration of a subsequent dose. 最大 Values ​​are reported in units of pg / mL or picograms per milliliter.

[0050] As used herein, the term "percent change" is used to quantify the change in a patient's eosinophil count upon administration of a formulation containing Compound I. The percent change is calculated by multiplying the patient's baseline (screening) eosinophil count (X) by the following formula: i ) and the eosinophil count (X f ) and is calculated using

number

[0051] As can be seen, a negative percent change indicates that the patient's eosinophil count decreased upon administration of the formulation containing Compound I.

[0052] formulation As discussed in WO 2011 / 051452, (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile is a potent JAK2 and JAK3 inhibitor that shows clinical promise in the treatment of respiratory conditions such as asthma and COPD, and inflammatory processes associated with eosinophilic and non-eosinophilic inflammation. This compound has the following formula (see WO 2016 / 124464) and is also referred to herein as Compound I. [ka]

[0053] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising Compound I or a pharmaceutically acceptable salt, solvate, clathrate, or co-crystal thereof, one or more fillers, one or more glidants, and one or more lubricants.

[0054] The formulation may include Compound I in any suitable solid form, including amorphous, crystalline, or a combination thereof. For example, Compound I may exhibit any suitable crystalline form. Representative crystalline forms include one or more of the crystalline forms described in WO2016 / 124464 (WO2016 / 124464 is incorporated herein by reference in its entirety for all purposes).

[0055] In some embodiments, the present disclosure provides the following compound I [ka] or a pharmaceutically acceptable salt thereof, lactose, and magnesium stearate.

[0056] In one embodiment, provided herein is a dry powder pharmaceutical formulation prepared by any of the methods disclosed herein.

[0057] In one aspect, provided herein: (a) (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile [ka] or a pharmaceutically acceptable salt thereof, (b) magnesium stearate, and (c) Providing a pharmaceutical formulation comprising lactose.

[0058] In one embodiment, the formulation comprises: (a) 20.0 to 25.0% by weight of Compound I or a pharmaceutically acceptable salt thereof; (b) 0.5 to 5.0 wt. % magnesium stearate, and (c) Contains 75.0 to 80.0% by weight of lactose.

[0059] In another embodiment, the formulation comprises: (a) 0.3 to 20.0% by weight of Compound I or a pharmaceutically acceptable salt thereof; (b) 0.3 to 10.0 wt. % magnesium stearate, and (c) Contains 70.0 to 99.4% by weight of lactose.

[0060] In another embodiment, the formulation comprises: (a) 0.4 to 13.0% by weight of Compound I or a pharmaceutically acceptable salt thereof; (b) 0.4 to 7.0 wt. % magnesium stearate, and (c) Contains 80.0 to 89.0% by weight of lactose.

[0061] In another embodiment, the formulation comprises: (a) 0.5 to 11.0 wt. % of Compound I or a pharmaceutically acceptable salt thereof; (b) 0.5 to 2.0 wt. % magnesium stearate, and (c) Contains 87.0 to 99.0% by weight of lactose.

[0062] In yet another embodiment, the formulation comprises: (a) about 1.1% by weight of Compound I or a pharmaceutically acceptable salt thereof; (b) about 1.0% by weight of magnesium stearate, and (c) contains about 97.9% lactose by weight.

[0063] In yet another embodiment, the formulation comprises: (a) about 10.3% by weight of Compound I or a pharmaceutically acceptable salt thereof; (b) about 1.2% by weight of magnesium stearate, and (c) Contains about 88.5% lactose by weight.

[0064] In one embodiment, the formulation comprises: (a) 1.0 to 5.0 mg of Compound I or a pharmaceutically acceptable salt thereof; (b) 0.1 to 1.0 mg of magnesium stearate, and (c) Contains 15.0 to 37.0 mg of lactose.

[0065] In another embodiment, the formulation comprises: (a) 0.1 to 1.0 mg of Compound I; (b) 0.1 to 1.0 mg of magnesium stearate, and (c) Contains 18.0 to 20.0 mg of lactose.

[0066] In yet another embodiment, the formulation comprises: (a) about 0.2 mg of Compound I or a pharmaceutically acceptable salt thereof; (b) about 0.2 mg magnesium stearate, and (c) Contains approximately 19.6 mg of lactose.

[0067] In yet another embodiment, the formulation comprises: (a) about 2.1 mg of Compound I or a pharmaceutically acceptable salt thereof; (b) about 0.3 mg magnesium stearate, and (c) Contains approximately 17.7 mg of lactose.

[0068] In one embodiment, the formulation comprises: (a) about 4.1 mg of Compound I or a pharmaceutically acceptable salt thereof; (b) about 0.5 mg magnesium stearate, and (c) Contains approximately 35.4 mg of lactose.

[0069] In one aspect, provided herein: 100% by weight of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile [ka] or a pharmaceutically acceptable salt thereof.

[0070] In another aspect, provided herein are (a) (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile [ka] or a pharmaceutically acceptable salt thereof with magnesium stearate; and (b) providing a pharmaceutical formulation comprising a second pre-blend of lactose and magnesium stearate;

[0071] In one embodiment, the first pre-blend contains 1.0 to 15.0% by weight magnesium stearate. In another embodiment, the first pre-blend contains 1.0 to 11.0% by weight magnesium stearate. In one embodiment, the first pre-blend contains about 6.5% by weight magnesium stearate.

[0072] In yet another embodiment, the first pre-mix contains 1.0-11.0% by weight magnesium stearate, and the second pre-mix contains 0.2-10.0% by weight magnesium stearate. In yet another embodiment, the first pre-mix contains 1.0-11.0% by weight magnesium stearate, and the second pre-mix contains 0.2-5.0% by weight magnesium stearate. In one embodiment, the first pre-mix contains 5.0-11.0% by weight magnesium stearate, and the second pre-mix contains 0.2-10.0% by weight magnesium stearate. In another embodiment, the first pre-mix contains about 6.5% by weight magnesium stearate, and the second pre-mix contains 0.2-10.0% by weight magnesium stearate.

[0073] In one embodiment, the formulation is prepared as a bulk powder.

[0074] In another embodiment, the formulation is prepared as a capsule or blister.

[0075] In one embodiment, the formulation is prepared as a capsule.

[0076] In yet another embodiment, the formulation comprises a bulk powder prepared without the use of plastic powder handling materials.

[0077] In yet another embodiment, the formulation comprises a capsule prepared without the use of plastic powder handling materials.

[0078] In one embodiment, the formulation is prepared without the use of plastic powder handling materials such as plastic spatulas, plastic scoops, or plastic transfer bags.

[0079] In another embodiment, the formulation is prepared without the use of a plastic transfer bag, such as a ChargeBag®.

[0080] In yet another embodiment, the formulation is prepared using stainless steel powder handling materials.

[0081] In yet another embodiment, the formulation is prepared using stainless steel powder handling materials, such as a stainless steel spatula, a stainless steel scoop, a stainless steel funnel, or a stainless steel container.

[0082] In some embodiments, the formulation is prepared as a capsule or bulk powder. In some embodiments, the formulation is prepared as a capsule. In some embodiments, the formulation is prepared as a bulk powder.

[0083] In some embodiments, the formulation is prepared as a capsule or blister. In some embodiments, the formulation is prepared as a blister.

[0084] In some embodiments, the formulation comprises about 0.5% to about 11.0% by weight of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 0.9% to about 1.3% by weight of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 9.5% to about 10.8% by weight of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 1.1% by weight of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 10.3% by weight of Compound I or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the formulation comprises about 87.0% to about 99.0% lactose by weight. In some embodiments, the formulation comprises about 88.0% to about 89.0% lactose by weight. In some embodiments, the formulation comprises about 97.0% to about 98.0% lactose by weight. In some embodiments, the formulation comprises about 88.5% lactose by weight. In some embodiments, the formulation comprises about 97.9% lactose by weight.

[0086] In some embodiments, the formulation comprises about 0.5% to about 2.0% by weight of magnesium stearate. In some embodiments, the formulation comprises about 0.8% to about 1.4% by weight of magnesium stearate. In some embodiments, the formulation comprises about 1.0% by weight of magnesium stearate. In some embodiments, the formulation comprises about 1.2% by weight of magnesium stearate.

[0087] In some embodiments, the formulation comprises about 0.5% to about 11% by weight of Compound I or a pharmaceutically acceptable salt thereof, about 87.0% to about 99.0% by weight of lactose, and about 0.5% to about 2.0% by weight of magnesium stearate.

[0088] In some embodiments, the formulation comprises about 1.1% by weight of Compound I or a pharmaceutically acceptable salt thereof, about 97.9% by weight of lactose, and about 1.0% by weight of magnesium stearate.

[0089] In some embodiments, the formulation comprises about 10.3% by weight of Compound I or a pharmaceutically acceptable salt thereof, about 88.5% by weight of lactose, and about 1.2% by weight of magnesium stearate.

[0090] Any suitable form of lactose can be used in the formulations described herein. Crystalline lactose, amorphous lactose, and mixtures thereof are suitable for use in the formulations of the present disclosure. In some embodiments, the lactose is a spray-dried mixture of crystalline lactose and amorphous lactose.

[0091] Any suitable form of magnesium stearate can be used in the formulations described herein. Several types and grades of magnesium stearate are suitable for use in the formulations of the present disclosure. Thus, magnesium stearate with different specific surface areas and different median particle sizes can be used in the formulations disclosed herein.

[0092] In some embodiments, the formulation is prepared for oral administration via inhaler (e.g., tablet or capsule). In some embodiments, the formulation is enclosed in a capsule. In some embodiments, the formulation is enclosed in a blister. In some embodiments, the formulation is prepared as a bulk powder.

[0093] In some embodiments, the formulation is prepared so that Compound I is present in an amount ranging from about 0.1 mg to about 4.2 mg. In some embodiments, Compound I is present in an amount of about 0.2 mg, about 2.0 mg, or about 4.0 mg. In some embodiments, Compound I is present in an amount of about 0.2 mg. In some embodiments, Compound I is present in an amount of about 2.0 mg. In some embodiments, Compound I is present in an amount of about 4.0 mg.

[0094] In some embodiments, the formulation is prepared so that Compound I is present in an amount of about 0.15 mg to about 0.25 mg. Thus, in one embodiment, the formulation comprises about 0.2 mg of Compound I, about 19.6 mg of lactose, and about 0.2 mg of magnesium stearate. In some embodiments, the formulation is prepared as a tablet or capsule containing 0.2 mg of active ingredient. In some embodiments, the formulation is prepared as a capsule containing 0.2 mg of active ingredient.

[0095] In some embodiments, the formulation is prepared so that Compound I is present in an amount of about 1.5 to 2.5 mg. Thus, in some embodiments, the formulation comprises about 2.0 mg of Compound I, about 17.7 mg of lactose, and about 0.3 mg of magnesium stearate. In some embodiments, the formulation is prepared as a tablet or capsule containing 2.0 mg of active ingredient. In some embodiments, the formulation is prepared as a capsule containing 2.0 mg of active ingredient.

[0096] In some embodiments, the formulation is prepared so that Compound I is present in an amount of about 3.5 to 4.5 mg. Thus, in some embodiments, the formulation comprises about 4.0 mg of Compound I, about 35.4 mg of lactose, and about 0.5 mg of magnesium stearate. In some embodiments, the formulation is prepared as a tablet or capsule containing 4.0 mg of active ingredient. In some embodiments, the formulation is prepared as a capsule containing 4.0 mg of active ingredient.

[0097] Additional fillers or diluents for use in the formulations of the present disclosure include fillers or diluents typically used in pharmaceutical formulations. Examples of fillers or diluents for use in accordance with the present disclosure include, but are not limited to, sugars such as lactose (e.g., anhydrous lactose, directly compressible anhydrous lactose, lactose monohydrate, modified lactose monohydrate), dextrose, glucose, sucrose, cellulose, starch, and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonate, magnesium carbonate, microcrystalline cellulose, combinations thereof, and the like. In some embodiments, the filler or diluent is lactose, microcrystalline cellulose, or a combination thereof. In some embodiments, the filler or diluent is trehalose.

[0098] The formulations of the present disclosure may also contain additional additives such as surfactants, polymers, and binders.Surfactants suitable for use in the formulations of the present disclosure include surfactants commonly used in pharmaceutical formulations.Examples of surfactants include, but are not limited to, ionic and nonionic surfactants or wetting agents commonly used in pharmaceutical formulations, such as ethoxylated castor oil, polyglycolized glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides or their ethoxylated derivatives, diglycerides or their polyoxyethylene derivatives, docusate sodium, sodium lauryl sulfate, cholic acid or its derivatives, lecithin, phospholipids, and combinations thereof.

[0099] The safety and efficacy of solid pharmaceutical products, as well as their robust performance, are ensured by meeting specified critical quality attributes (CQAs). Among them, the content uniformity (CU) of a drug product is the most important. Content uniformity is defined as a measure of how evenly the API is distributed throughout the mixture. A blend with excellent content uniformity has the same concentration of API throughout the blend (e.g., top, middle, and bottom). Content uniformity is measured by taking multiple samples from various locations throughout the blend and analyzing each sample by HPLC or a similar technique to determine the API concentration in each sample. Content uniformity is expressed as the percent relative standard deviation (RSD) of the pooled samples based on the concentration of the drug mixture.

[0100] In one embodiment, the content uniformity of a pharmaceutical formulation of Compound I has a percent relative standard deviation (RSD) of about 5% or less. In another embodiment, the content uniformity of a pharmaceutical formulation of Compound I has an RSD of about 4.0% or less. In yet another embodiment, the content uniformity of a pharmaceutical formulation of Compound I has an RSD of about 3.0% or less.

[0101] In yet another embodiment, the content uniformity of the pharmaceutical formulation of Compound I has an RSD of about 2.0% or less. In one embodiment, the content uniformity of the pharmaceutical formulation of Compound I has an RSD of about 1.5% or less. In another embodiment, the content uniformity of the pharmaceutical formulation of Compound I has an RSD of about 1.0% or less. In yet another embodiment, the content uniformity of the pharmaceutical formulation of Compound I has an RSD of about 0.5% or less.

[0102] Compound I is typically administered as a pharmaceutical formulation together with a pharmaceutically acceptable carrier or excipient. In one embodiment, the present disclosure relates to a pharmaceutical formulation of Compound I comprising one or more pharmaceutically acceptable excipients. Suitable compositions may be in the form of a tablet, a capsule, or an inhalable composition. In one embodiment, the present disclosure provides a capsule comprising Compound I. In one embodiment, the present disclosure provides a capsule filled with a formulation comprising Compound I. In one embodiment, the present disclosure provides a blister filled with a formulation comprising Compound I. In one embodiment, the present disclosure provides an inhalable composition comprising Compound I.

[0103] The formulation can be delivered by a dry powder inhaler (DPI) for the treatment of respiratory diseases. When administered by inhalation using a dry powder inhaler, Compound I can be administered as a dry powder formulation containing one or more carrier substances. Suitable inhalation carriers are known in the art, and in one embodiment, include crystalline sugars such as monosaccharides or disaccharides. In one embodiment, the carrier is lactose. Compound I can also be administered as a dry powder formulation without a carrier substance.

[0104] The dry powder formulations of the present disclosure may also have additional additives, such as force control agents. Force control agents are additives that reduce cohesion between fine particles in the powder formulation, thereby promoting deagglomeration when the powder is dispensed from an inhaler. Suitable force control agents, such as magnesium stearate, are known in the art to enhance the stability of dry powder formulations. In one embodiment, the force control agent is a metal stearate, such as magnesium stearate.

[0105] The dry powder formulations of the present disclosure can be administered using a single-dose dry powder inhaler or a multi-dose dry powder inhaler. In a non-limiting example, the dry powder formulations of the present disclosure can be administered using various dry powder inhalers, such as GyroHaler® or Miat®, Monodose RS01, or a lever-operated inhaler such as that disclosed in WO 2009 / 092770. In another non-limiting example, the dry powder formulations of the present disclosure can be administered using an open-inhale-close device. In a further embodiment, the present disclosure provides a kit comprising an inhaler in combination with a formulation provided herein. In a further embodiment, the present disclosure provides a kit comprising a dry powder inhaler in combination with a pharmaceutical formulation provided herein. In one embodiment, the present disclosure provides a kit comprising a Miat single-dose RS01 dry powder inhaler in combination with a pharmaceutical formulation provided herein.

[0106] For pulmonary administration, the size of API particles is crucial in determining the site of absorption. To be transported deep into the lungs, API particles must be very fine, e.g., have a mass median aerodynamic diameter of less than 10 μm. Particles with an aerodynamic diameter greater than 10 μm are likely to impact the pharyngeal wall and typically do not reach the lungs. Particles with an aerodynamic diameter between 5 μm and 0.5 μm typically deposit in the respiratory bronchioles, while smaller particles with an aerodynamic diameter between 2 μm and 0.05 μm are more likely to deposit in the alveoli.

[0107] In another embodiment, the formulation is suitable for aerosol delivery to a subject.

[0108] In yet another embodiment, when aerosolized, the mass median aerodynamic diameter (MMAD) is about 5.0 μm or less (e.g., 0.5-5.0 μm, 1.0-4.0 μm, 1.5-3.0 μm, or 1.5-2.5 μm). In yet another embodiment, when aerosolized, the mass median aerodynamic diameter (MMAD) is about 1.9 μm. In another embodiment, when aerosolized, the mass median aerodynamic diameter (MMAD) is about 1.8 μm.

[0109] Another important parameter for inhaled dry powder formulations is dose delivery efficiency, as measured by the fine particle fraction (FPF). The FPF therefore provides an in vitro indication of the efficiency of the device / formulation in delivering the API to the lungs.

[0110] In one embodiment, when aerosolized, Compound I has a fine particle fraction (FPF) of about 60% or greater (e.g., 60-100%, 65-90%, 65-85%, 65-80%, 70-80%, or 70-78%). In another embodiment, when aerosolized, Compound I has an FPF of about 72.5-77.5%.

[0111] The proportion of each metered dose that is composed of drug particles of the correct size (MMAD) for deposition at the desired site in the lung must also be uniform (stable) (i.e., within a specified range). This proportion is known as the fine particle mass (FPM) and represents the proportion of the metered dose that is composed of drug particles having an MMAD within the range of about 1 micron to about 5 microns. As is well known in the art, the FPM of a pMDI can be determined with a cascade impactor, such as the Next Generation Impactor (NCI). The FPM is the amount of the metered dose collected at a particular stage of the cascade impactor (e.g., NGI).

[0112] In yet another embodiment, when a capsule containing about 1.0-3.0 mg of Compound I is aerosolized, the fine particle mass (FPM) of Compound I is 900-1800 μg. In yet another embodiment, when a capsule containing about 1.0-3.0 mg of Compound I is aerosolized, the fine particle mass (FPM) of Compound I is 900-1500 μg. In yet another embodiment, when a capsule containing about 1.0-3.0 mg of Compound I is aerosolized, the fine particle mass (FPM) of Compound I is 900-1200 μg.

[0113] In yet another embodiment, when a capsule containing about 3.0-5.0 mg of Compound I is aerosolized, the FPM of Compound I is 1750-2450 μg. In yet another embodiment, when a capsule containing about 3.0-5.0 mg of Compound I is aerosolized, the FPM of Compound I is 1750-2350 μg. In yet another embodiment, when a capsule containing about 3.0-5.0 mg of Compound I is aerosolized, the FPM of Compound I is 1850-2250 μg. In yet another embodiment, when a capsule containing about 3.0-5.0 mg of Compound I is aerosolized, the FPM of Compound I is 1950-2250 μg.

[0114] For dry powder inhalers (DPIs), it is important to balance the flow characteristics of the dry powder within the inhaler with the plume characteristics upon inhalation. Coarse carrier particles, usually lactose, are used to aid the flow characteristics of the medication, but it is important to ensure that the active ingredient separates from the coarse carrier upon inhalation, allowing fine particles of the active ingredient to be taken up in the lungs. It is important that this process occurs in a consistent manner to provide an adequate dose over the life of the inhaler. That is, the inhaler must actually provide a consistent delivered dose and fine particle mass from the first dose to the last dose.

[0115] In yet another embodiment, the delivered dose of Compound I when aerosolized is at least about 80% (e.g., 60-100%, 65-100%, 70-100%, and 75-90%) of the target dose. In yet another embodiment, the delivered dose of Compound I when aerosolized is 78-88% of the target dose.

[0116] In one embodiment, compound I has a copper Kα1 activity of: Approximately 8.25°, Approximately 13.25°, Approximately 15.40°, Approximately 17.65°, and It is a polymorph (Form II) with a diffraction angle (2θ) of about 25.39°.

[0117] Polymorph II In one embodiment of the formulations, methods of preparation, methods of treatment, and methods of reducing FeNO described herein, (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I) is polymorph II having X-ray powder diffraction peak data according to the following table: [Table 1]

[0118] In one embodiment, compound I has a copper Kα1 activity of: Approximately 8.25°, Approximately 13.25°, Approximately 15.40°, Approximately 17.65°, and It is a polymorph (Form II) with a diffraction angle (2θ) of about 25.39°.

[0119] This polymorph and its corresponding method of preparation are disclosed in U.S. Patent No. 10,087,196, which is incorporated herein by reference in its entirety. Form II is further characterized by an endothermic onset at 239°C as measured by differential scanning calorimetry.

[0120] How to use Compound I has been shown to be a potent inhibitor of JAK family enzymes, specifically JAK1, JAK2, JAK3, and TYK2. For example, the biological activity of this compound is described in WO2011 / 051452 (incorporated herein by reference in its entirety). Inhibition of the JAK family of enzymes may inhibit the signal transduction of many key pro-inflammatory cytokines. Furthermore, JAK inhibition offers an opportunity to block inflammatory pathways involved in the development of multiple diseases. Such multiple diseases include diseases associated with eosinophilic and non-eosinophilic inflammation, including respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Therefore, the formulations of the present disclosure are useful in treating diseases associated with eosinophilic and non-eosinophilic inflammation, as defined herein, and respiratory diseases such as asthma and chronic obstructive pulmonary disease.

[0121] Compound I and formulations containing Compound I are useful in the treatment of asthma and COPD, as well as other inflammatory diseases associated with eosinophilic and non-eosinophilic inflammation.

[0122] In one aspect, provided herein is a method of treating asthma, COPD, or an inflammatory disorder associated with eosinophilic or non-eosinophilic inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof.

[0123] In one embodiment, the formulation further comprises lactose and magnesium stearate.

[0124] In one aspect, provided herein is a method of treating a respiratory disorder, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical formulation disclosed herein.

[0125] In some embodiments, the respiratory disease is asthma. In some embodiments, the respiratory disease is COPD. In some embodiments, the respiratory disease is associated with eosinophilic inflammation or non-eosinophilic inflammation. In some embodiments, the respiratory disease associated with eosinophilic inflammation or non-eosinophilic inflammation is asthma, COPD, nasal polyps, rhinitis, fibrotic lung disease, interstitial lung disease, or pulmonary hypertension. In some embodiments, the respiratory disease associated with eosinophilic inflammation or non-eosinophilic inflammation is asthma, nasal polyps, rhinitis, fibrotic lung disease, interstitial lung disease, or pulmonary hypertension. In some embodiments, the respiratory disease associated with eosinophilic inflammation or non-eosinophilic inflammation is nasal polyps. In some embodiments, the respiratory disease associated with eosinophilic inflammation or non-eosinophilic inflammation is rhinitis. In some embodiments, the respiratory disease associated with eosinophilic inflammation or non-eosinophilic inflammation is fibrotic lung disease. In some embodiments, the respiratory disease associated with eosinophilic or non-eosinophilic inflammation is interstitial lung disease, hi some embodiments, the respiratory disease associated with eosinophilic or non-eosinophilic inflammation is pulmonary hypertension.

[0126] In some embodiments, the respiratory disease associated with eosinophilic inflammation or non-eosinophilic inflammation is mild, moderate, or severe asthma. In some embodiments, the formulation is administered once daily. In some embodiments, the formulation is administered twice daily. In some embodiments, the subject is a human. In some embodiments, the subject is ICS-naive.

[0127] In one embodiment, the method further comprises administering at least one of an inhaled corticosteroid, a long-acting beta-adrenergic receptor agonist (LABA), a long-acting muscarinic antagonist (LAMA), or a short-acting beta-agonist (SABA).

[0128] In another aspect, provided herein are methods of treating asthma, COPD, or an inflammatory disease associated with eosinophilic or non-eosinophilic inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation of the present disclosure. In some embodiments, the inflammatory disease associated with eosinophilic or non-eosinophilic inflammation is eosinophilic asthma, nasal polyposis, rhinitis, fibrotic lung disease, or interstitial lung disease.

[0129] In some embodiments, the inflammatory disease associated with eosinophilic inflammation or non-eosinophilic inflammation is eosinophilic asthma, nasal polyps, rhinitis, fibrotic lung disease, interstitial lung disease, or pulmonary hypertension.

[0130]

[0013] In one aspect, provided herein is a method of treating asthma, COPD, or an inflammatory disorder associated with eosinophilic or non-eosinophilic inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt or co-crystal thereof.

[0131] In one aspect, provided herein is a method of treating asthma, COPD, or an inflammatory disorder associated with eosinophilic or non-eosinophilic inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof.

[0132] In one embodiment, the pharmaceutical formulation further comprises lactose and magnesium stearate.

[0133] In another embodiment, the subject has mild asthma. In yet another embodiment, the subject has moderate asthma. In yet another embodiment, the subject has moderate to severe asthma. In one embodiment, the subject's moderate to severe asthma is characterized by low Th2 expression. In one embodiment, the subject's moderate to severe asthma is characterized by high Th2 expression.

[0134] In another embodiment, the subject is a human. In some embodiments, the formulation comprising Compound I acts locally in the respiratory tract.

[0135] In yet another embodiment, administration of the formulation provides an AUC of 30,000 h·pg / mL to 1,500,000 h·pg / mL. 0~∞ In yet another embodiment, administration of the formulation results in an AUC 0~∞ In one embodiment, administration of the formulation results in a mean AUC of about 358,700 h·pg / mL. 0~∞ In another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In yet another embodiment, the subject has mild asthma.

[0136] In yet another embodiment, administration of the formulation provides an AUC 0~∞ In one embodiment, administration of the formulation results in a mean AUC of about 439,000 h·pg / mL. 0~∞ In another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In yet another embodiment, the subject has moderate to severe asthma.

[0137] In yet another embodiment, administration of the formulation provides an AUC of 340,000 h·pg / mL to 1,400,000 h·pg / mL. 0~∞ In one embodiment, administration of the formulation results in a mean AUC of about 747,000 h·pg / mL. 0~∞In another embodiment, the subject is administered about 8.0 mg of Compound I twice daily. In yet another embodiment, the subject has mild asthma.

[0138] In yet another embodiment, administration of the formulation provides an AUC 0~∞ In one embodiment, administration of the formulation results in an AUC 0~∞ In another embodiment, administration of the formulation results in a mean AUC 0~∞ In yet another embodiment, the subject is administered about 0.6 mg of Compound I once daily. In yet another embodiment, the subject has mild asthma.

[0139] In one embodiment, administration of the formulation provides an AUC of 49,000 h·pg / mL to 146,000 h·pg / mL. 0~∞ In another embodiment, administration of the formulation results in a mean AUC 0~∞ In yet another embodiment, the subject is administered about 2.0 mg of Compound I once daily. In yet another embodiment, the subject has mild asthma.

[0140] In yet another embodiment, administration of the formulation provides an AUC of 30,000 h·pg / mL to 1,500,000 h·pg / mL. 0~最終非ゼロ In yet another embodiment, administration of the formulation results in an AUC 0~最終非ゼロ In one embodiment, administration of the formulation results in a mean AUC of about 355,000 h·pg / mL. 0~最終非ゼロ In another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In yet another embodiment, the subject has mild asthma.

[0141] In yet another embodiment, administration of the formulation provides an AUC 0~最終非ゼロIn one embodiment, administration of the formulation results in a mean AUC of about 438,000 h·pg / mL. 0~最終非ゼロ In another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In yet another embodiment, the subject has moderate to severe asthma.

[0142] In yet another embodiment, administration of the formulation provides an AUC of 340,000 h·pg / mL to 1,400,000 h·pg / mL. 0~最終非ゼロ In one embodiment, administration of the formulation results in a mean AUC of about 745,000 h·pg / mL. 0~最終非ゼロ In another embodiment, the subject is administered about 8.0 mg of Compound I twice daily. In yet another embodiment, the subject has mild asthma.

[0143] In yet another embodiment, administration of the formulation provides an AUC 0~最終非ゼロ In one embodiment, administration of the formulation results in an AUC 0~最終非ゼロ In another embodiment, administration of the formulation results in a mean AUC 0~最終非ゼロ In yet another embodiment, the subject is administered about 0.6 mg of Compound I once daily. In yet another embodiment, the subject has mild asthma.

[0144] In one embodiment, administration of the formulation provides an AUC of 47,000 h·pg / mL to 146,000 h·pg / mL. 0~最終非ゼロ In another embodiment, administration of the formulation results in a mean AUC 0~最終非ゼロ In yet another embodiment, the subject is administered about 2.0 mg of Compound I once daily. In yet another embodiment, the subject has mild asthma.

[0145] In yet another embodiment, administration of the formulation provides an AUC 投与間隔In yet another embodiment, administration of the formulation results in an AUC 投与間隔 In one embodiment, administration of the formulation results in a mean AUC of about 237,000 h·pg / mL. 投与間隔 In another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In yet another embodiment, the subject has mild asthma.

[0146] In yet another embodiment, administration of the formulation provides an AUC 投与間隔 In one embodiment, administration of the formulation results in a mean AUC of about 278,000 h·pg / mL. 投与間隔 In another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In yet another embodiment, the subject has moderate to severe asthma.

[0147] In yet another embodiment, administration of the formulation provides an AUC of 258,000 h·pg / mL to 832,000 h·pg / mL. 投与間隔 In one embodiment, administration of the formulation results in a mean AUC of about 458,000 h·pg / mL. 投与間隔 In another embodiment, the subject is administered about 8.0 mg of Compound I twice daily. In yet another embodiment, the subject has mild asthma.

[0148] In yet another embodiment, administration of the formulation provides an AUC 投与間隔 In one embodiment, administration of the formulation results in an AUC 投与間隔 In another embodiment, administration of the formulation results in a mean AUC 投与間隔 In yet another embodiment, the subject is administered about 0.6 mg of Compound I once daily. In yet another embodiment, the subject has mild asthma.

[0149] In one embodiment, administration of the formulation provides an AUC of 40,000 h·pg / mL to 128,000 h·pg / mL. 投与間隔 In another embodiment, administration of the formulation results in a mean AUC 投与間隔 In yet another embodiment, the subject is administered about 2.0 mg of Compound I once daily. In yet another embodiment, the subject has mild asthma.

[0150] In yet another embodiment, administration of the formulation provides an AUC 0~12時間 In yet another embodiment, administration of the formulation results in an AUC 0~12時間 In one embodiment, administration of the formulation results in a mean AUC of about 237,000 h·pg / mL. 0~12時間 In another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In yet another embodiment, the subject has mild asthma.

[0151] In yet another embodiment, administration of the formulation provides an AUC of 258,000 h·pg / mL to 832,000 h·pg / mL. 0~12時間 In one embodiment, administration of the formulation results in a mean AUC of about 458,000 h·pg / mL. 0~12時間 In another embodiment, the subject is administered about 8.0 mg of Compound I twice daily. In yet another embodiment, the subject has mild asthma.

[0152] In yet another embodiment, administration of the formulation provides an AUC 0~12時間 In one embodiment, administration of the formulation results in an AUC 0~12時間 In another embodiment, administration of the formulation results in a mean AUC 0~12時間 In yet another embodiment, the subject is administered about 0.6 mg of Compound I once daily. In yet another embodiment, the subject has mild asthma.

[0153] In one embodiment, administration of the formulation provides an AUC of 28,000 h·pg / mL to 90,000 h·pg / mL. 0~12時間 In another embodiment, administration of the formulation results in a mean AUC 0~12時間 In yet another embodiment, the subject is administered about 2.0 mg of Compound I once daily. In yet another embodiment, the subject has mild asthma.

[0154] In yet another embodiment, administration of the formulation provides an AUC of 20,000 h·pg / mL to 1,200,000 h·pg / mL. 0~24時間 In yet another embodiment, administration of the formulation results in an AUC 0~24時間 In one embodiment, administration of the formulation results in a mean AUC of about 299,000 h·pg / mL. 0~24時間 In another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In yet another embodiment, the subject has mild asthma.

[0155] In yet another embodiment, administration of the formulation provides an AUC 0~24時間 In one embodiment, administration of the formulation results in a mean AUC of about 365,000 h·pg / mL. 0~24時間 In another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In yet another embodiment, the subject has moderate to severe asthma.

[0156] In yet another embodiment, administration of the formulation provides an AUC 0~24時間 In one embodiment, administration of the formulation results in a mean AUC of about 612,000 h·pg / mL. 0~24時間 In another embodiment, the subject is administered about 8.0 mg of Compound I twice daily. In yet another embodiment, the subject has mild asthma.

[0157] In yet another embodiment, administration of the formulation provides an AUC 0~24時間 In one embodiment, administration of the formulation results in an AUC 0~24時間 In another embodiment, administration of the formulation results in a mean AUC 0~24時間 In yet another embodiment, the subject is administered about 0.6 mg of Compound I once daily. In yet another embodiment, the subject has mild asthma.

[0158] In one embodiment, administration of the formulation provides an AUC of 40,000 h·pg / mL to 128,000 h·pg / mL. 0~24時間 In another embodiment, administration of the formulation results in a mean AUC 0~24時間 In yet another embodiment, the subject is administered about 2.0 mg of Compound I once daily. In yet another embodiment, the subject has mild asthma.

[0159] In one embodiment, administration of the formulation provides a C of 200 pg / mL to 50,000 pg / mL. トラフ In another embodiment, administration of the formulation results in a C of 400 pg / mL to 17,000 pg / mL. トラフ In yet another embodiment, administration of the formulation results in a mean C of about 10,000 pg / mL. トラフ In yet another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In one embodiment, the subject has mild asthma.

[0160] In another embodiment, administration of the formulation provides a C of 1,000 pg / mL to 25,000 pg / mL. トラフ In yet another embodiment, administration of the formulation results in a mean C of about 11,000 pg / mL. トラフ In yet another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In one embodiment, the subject has moderate to severe asthma.

[0161] In another embodiment, administration of the formulation provides a C of 5,000 pg / mL to 42,000 pg / mL. トラフ In yet another embodiment, administration of the formulation results in a mean C of about 22,000 pg / mL. トラフ In yet another embodiment, the subject is administered about 8.0 mg of Compound I twice daily. In one embodiment, the subject has mild asthma.

[0162] In another embodiment, administration of the formulation provides a C of 20 pg / mL to 3,000 pg / mL. トラフ In yet another embodiment, administration of the formulation results in a C of 30 pg / mL to 3,000 pg / mL. トラフ In yet another embodiment, administration of the formulation results in a mean C of about 375 pg / mL. トラフ In one embodiment, the subject is administered about 0.6 mg of Compound I once daily. In another embodiment, the subject has mild asthma.

[0163] In yet another embodiment, administration of the formulation provides a C of 400 pg / mL to 2,000 pg / mL. トラフ In yet another embodiment, administration of the formulation results in a mean C of about 975 pg / mL. トラフ In one embodiment, the subject is administered about 2.0 mg of Compound I once daily. In another embodiment, the subject has mild asthma.

[0164] In one embodiment, administration of the formulation is at a maximum concentration (C 最大 In another embodiment, administration of the formulation results in a C of 6,000 pg / mL to 49,000 pg / mL. 最大 In yet another embodiment, administration of the formulation results in a mean C of about 31,000 pg / mL. 最大 In yet another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In one embodiment, the subject has mild asthma.

[0165] In another embodiment, administration of the formulation provides a C of 13,000 pg / mL to 65,000 pg / mL. 最大 In yet another embodiment, administration of the formulation results in a mean C of about 38,000 pg / mL. 最大 In yet another embodiment, the subject is administered about 4.0 mg of Compound I twice daily. In one embodiment, the subject has moderate to severe asthma.

[0166] In another embodiment, administration of the formulation provides a C of 43,000 pg / mL to 93,000 pg / mL. 最大 In yet another embodiment, administration of the formulation results in a mean C of about 60,000 pg / mL. 最大 In yet another embodiment, the subject is administered about 8.0 mg of Compound I twice daily. In one embodiment, the subject has mild asthma.

[0167] In another embodiment, administration of the formulation provides a C of 300 pg / mL to 15,000 pg / mL. 最大 In yet another embodiment, administration of the formulation results in a C of 900 pg / mL to 3,000 pg / mL. 最大 In yet another embodiment, administration of the formulation results in a mean C of about 2,000 pg / mL. 最大 In one embodiment, the subject is administered about 0.6 mg of Compound I once daily. In another embodiment, the subject has mild asthma.

[0168] In yet another embodiment, administration of the formulation provides a C of 3,000 pg / mL to 10,000 pg / mL. 最大 In yet another embodiment, administration of the formulation results in a mean C of about 6,000 pg / mL. 最大 In one embodiment, the subject is administered about 2.0 mg of Compound I once daily. In another embodiment, the subject has mild asthma.

[0169] In one embodiment, the above pharmacokinetic parameters can be measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and / or 20 days after administration of the formulation.

[0170] In yet another embodiment, administration of the formulation results in a decrease in the eosinophil percentage in induced sputum compared to pre-administration values. In yet another embodiment, administration of the formulation results in a decrease in the eosinophil percentage in induced sputum of 1.5% to 20%. In another embodiment, administration of the formulation results in an average decrease in the eosinophil percentage in induced sputum of about 7%.

[0171] In one embodiment, the reduction in the eosinophil percentage in induced sputum is at least about 2%. In another embodiment, the reduction in the eosinophil percentage in induced sputum is at least about 4%. In yet another embodiment, the reduction in the eosinophil percentage in induced sputum is at least about 6%. In yet another embodiment, the reduction in the eosinophil percentage in induced sputum is at least about 8%. In one embodiment, the reduction in the eosinophil percentage in induced sputum is at least about 10%. In another embodiment, the reduction in the eosinophil percentage in induced sputum is at least about 12%. In yet another embodiment, the reduction in the eosinophil percentage in induced sputum is at least about 14%. In yet another embodiment, the reduction in the eosinophil percentage in induced sputum is at least about 16%. In one embodiment, the reduction in the eosinophil percentage in induced sputum is at least about 18%. In another embodiment, the decrease in induced sputum eosinophil percentage is at least about 20%.

[0172] In yet another embodiment, administration of the formulation results in a percent change in induced sputum eosinophil percentage of -35% to -110%. In one embodiment, the average percent change in induced sputum eosinophil percentage is about -65%.

[0173] In another embodiment, the percentage change in the eosinophil ratio in induced sputum is at least about -45%. In yet another embodiment, the percentage change in the eosinophil ratio in induced sputum is at least about -50%. In yet another embodiment, the percentage change in the eosinophil ratio in induced sputum is at least about -55%. In one embodiment, the percentage change in the eosinophil ratio in induced sputum is at least about -60%. In another embodiment, the percentage change in the eosinophil ratio in induced sputum is at least about -65%. In yet another embodiment, the percentage change in the eosinophil ratio in induced sputum is at least about -70%. In yet another embodiment, the percentage change in the eosinophil ratio in induced sputum is at least about -75%. In one embodiment, the percentage change in the eosinophil ratio in induced sputum is at least about -80%. In another embodiment, the percentage change in the eosinophil ratio in induced sputum is at least about -85%. In yet another embodiment, the percentage change in eosinophil percentage in induced sputum is at least about -90%. In yet another embodiment, the percentage change in eosinophil percentage in induced sputum is at least about -95%. In yet another embodiment, the percentage change in eosinophil percentage in induced sputum is at least about -100%.

[0174] In yet another embodiment, the patient's induced sputum eosinophil percentage is reduced to less than about 3%. In yet another embodiment, the above change in induced sputum eosinophil percentage is achieved by administering about 4.0 mg of Compound I twice daily.

[0175] In yet another embodiment, administration of the formulation results in a decrease in the absolute eosinophil count in induced sputum compared to pre-administration values. In yet another embodiment, administration of the formulation results in a decrease in the absolute eosinophil count in induced sputum of 0.05x10 6 / g~0.40x10 6 In another embodiment, administration of the formulation reduces the absolute eosinophil count in induced sputum by an average of about 0.15x10 6 / g decrease.

[0176] In one embodiment, the reduction in absolute eosinophil count in induced sputum is at least about 0.05x10 6 / g. In another embodiment, the reduction in absolute eosinophil count in induced sputum is at least about 0.1 x 106 / g. In yet another embodiment, the reduction in absolute eosinophil count in induced sputum is at least about 0.15x10 6 In yet another embodiment, the reduction in absolute eosinophil count in induced sputum is at least about 0.2x10 6 / g. In one embodiment, the reduction in absolute eosinophil count in induced sputum is at least about 0.25x10 6 / g. In another embodiment, the reduction in absolute eosinophil count in induced sputum is at least about 0.3x10 6 In yet another embodiment, the reduction in absolute eosinophil count in induced sputum is at least about 0.35x10 6 / g.

[0177] In yet another embodiment, administration of the formulation results in a percent change in absolute eosinophil count in induced sputum of between -60% and -110%. In one embodiment, the average percent change in absolute eosinophil count in induced sputum is about -80%.

[0178] In another embodiment, the percent change in the absolute eosinophil count in induced sputum is at least about -65%. In one embodiment, the percent change in the absolute eosinophil count in induced sputum is at least about -70%. In yet another embodiment, the percent change in the absolute eosinophil count in induced sputum is at least about -75%. In yet another embodiment, the percent change in the absolute eosinophil count in induced sputum is at least about -80%. In one embodiment, the percent change in the absolute eosinophil count in induced sputum is at least about -85%. In another embodiment, the percent change in the absolute eosinophil count in induced sputum is at least about -90%. In yet another embodiment, the percent change in the absolute eosinophil count in induced sputum is at least about -95%. In yet another embodiment, the percent change in the absolute eosinophil count in induced sputum is at least about -100%. In one embodiment, the percent change in absolute eosinophil count in induced sputum is at least about -105%.

[0179] In another embodiment, the above-described change in absolute eosinophil count in induced sputum is effected by administering about 4.0 mg of Compound I twice daily.

[0180] In yet another embodiment, administration of the formulation results in a decrease in absolute serum eosinophil count compared to pre-administration values. In yet another embodiment, administration of the formulation results in a decrease in absolute serum eosinophil count of 0.01x10 9 / L~0.4x10 9 In another embodiment, administration of the formulation results in a reduction in absolute serum eosinophil count of about 0.15x10 / L. 9 / L decrease.

[0181] In one embodiment, the reduction in absolute serum eosinophil count is at least about 0.03 x 10 9 / L. In another embodiment, the reduction in absolute serum eosinophil count is at least about 0.05 x 10 9 In yet another embodiment, the reduction in absolute serum eosinophil count is at least about 0.1 x 10 9 / L. In yet another embodiment, the decrease in serum absolute eosinophil count difference is at least about 0.15 x 10 9 / L. In one embodiment, the reduction in absolute serum eosinophil count is at least about 0.2 x 10 9 / L. In another embodiment, the reduction in absolute serum eosinophil count is at least about 0.25 x 10 9 In yet another embodiment, the reduction in absolute serum eosinophil count is at least about 0.3 x 10 9 / L. In yet another embodiment, the reduction in absolute serum eosinophil count is at least about 0.35 x 10 9 / L. In one embodiment, the reduction in absolute serum eosinophil count is at least about 0.4 x 10 9 / L.

[0182] In yet another embodiment, administration of the formulation results in a percent change in serum absolute eosinophil count that is between -2% and -80%. In one embodiment, the mean percent change in serum absolute eosinophil count is about -29%.

[0183] In another embodiment, the percent change in absolute serum eosinophil count is at least about -4%. In yet another embodiment, the percent change in absolute serum eosinophil count is at least about -15%. In yet another embodiment, the percent change in absolute serum eosinophil count is at least about -25%. In one embodiment, the percent change in absolute serum eosinophil count is at least about -32%. In another embodiment, the percent change in absolute serum eosinophil count is at least about -40%. In yet another embodiment, the percent change in absolute serum eosinophil count is at least about -43%. In yet another embodiment, the percent change in absolute serum eosinophil count is at least about -45%. In one embodiment, the percent change in absolute serum eosinophil count is at least about -50%. In another embodiment, the percent change in absolute serum eosinophil count is at least about -54%. In yet another embodiment, the percent change in absolute serum eosinophil count is at least about -60%. In yet another embodiment, the percent change in absolute serum eosinophil count is at least about -65%. In yet another embodiment, the percent change in absolute serum eosinophil count is at least about -70%. In yet another embodiment, the percent change in absolute serum eosinophil count is at least about -74%. In one embodiment, the percent change in absolute serum eosinophil count is at least about -80%.

[0184] In another embodiment, the above-described change in absolute serum eosinophil count is effected by administering about 4.0 mg of Compound I twice daily.

[0185] Suitable doses for the treatment of asthma and other respiratory disorders are believed to be in the range of about 0.1 to about 100 mg / day of Compound I (e.g., about 0.2 to about 50 mg / day of active agent) for an average 70 kg human. Suitable doses include, for example, about 0.001 mg / kg or 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg.

[0186] In some embodiments, the subject is administered a formulation comprising Compound I at a dose of at least about 0.005 mg / kg. In some embodiments, the subject is administered a formulation comprising Compound I at a dose of at least about 0.001 mg / kg to about 1 mg / kg. In some embodiments, the subject is administered a formulation comprising Compound I at a dose of about 0.1 mg / kg to about 1 mg / kg (e.g., a formulation comprising Compound I, MgSt, and lactose). In some embodiments, the subject is administered a formulation comprising Compound I at a dose of about 0.01 mg / kg to about 0.1 mg / kg. In some embodiments, the subject is administered a formulation comprising Compound I at a dose of 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg, 12.0 mg, 16.0 mg, 48.0 mg, or 68.0 mg (e.g., a formulation comprising Compound I, MgSt, and lactose). In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of 0.2 mg, 0.6 mg, 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg, or 12.0 mg (e.g., a pharmaceutical formulation comprising Compound I, MgSt, and lactose). In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 0.2 mg. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 0.6 mg. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 2.0 mg. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 4.0 mg. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 6.0 mg. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 8.0 mg. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 12.0 mg.

[0187] In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at any of the above doses once daily or twice daily. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 0.6 mg once daily. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 2.0 mg once daily. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 4.0 mg once daily. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 4.0 mg twice daily. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 8.0 mg once daily. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 8.0 mg twice daily. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I at a dose of about 12.0 mg once daily.

[0188] In one aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, the methods comprising administering a therapeutically effective amount of any of the pharmaceutical formulations described herein in combination with at least one of a long-acting beta-adrenergic receptor agonist, a long-acting muscarinic antagonist, a short-acting beta-adrenergic receptor agonist, and an inhaled corticosteroid.

[0189] In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I (e.g., a pharmaceutical formulation comprising Compound I, MgSt, and lactose) in combination with at least one of a long-acting beta-adrenergic receptor agonist, a long-acting muscarinic antagonist, or an inhaled corticosteroid. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I and a long-acting beta-adrenergic receptor agonist. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I and a long-acting muscarinic antagonist. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I and an inhaled corticosteroid. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I and a short-acting beta-adrenergic receptor agonist. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I and a short-acting muscarinic antagonist.

[0190] In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I, an inhaled corticosteroid, and a long-acting beta-adrenergic receptor agonist. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I, a long-acting beta-adrenergic receptor agonist, and a long-acting muscarinic antagonist. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I, an inhaled corticosteroid, a long-acting beta-adrenergic receptor agonist, and a long-acting muscarinic antagonist. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I, a short-acting beta-adrenergic receptor agonist, and an inhaled corticosteroid. In some embodiments, the subject is administered a pharmaceutical formulation comprising Compound I, a short-acting beta-adrenergic receptor agonist, and a short-acting muscarinic antagonist. In some embodiments, the disease or disorder is asthma. In some embodiments, the disease or disorder is COPD.

[0191] Methods for reducing FeNO In one aspect, provided herein is a method of reducing exhaled nitric oxide (FeNO) levels in a subject by administering to a subject in need thereof a pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof.

[0192] In one aspect, provided herein is a method for reducing FeNO levels in a subject, the method comprising administering to a subject in need thereof a pharmaceutical formulation disclosed herein.

[0193] In another embodiment, the subject's FeNO concentration is reduced to at least about 35 ppb (ppb is parts per billion). In yet another embodiment, the subject's FeNO concentration is reduced to at least about 30 ppb. In yet another embodiment, the subject's FeNO concentration is reduced to at least about 35 ppb. In one embodiment, the subject's FeNO concentration is reduced to at least about 20 ppb. In another embodiment, the subject's FeNO concentration is reduced to at least about 15 ppb. In yet another embodiment, the subject's FeNO concentration is reduced to at least about 10 ppb. In one embodiment, the subject's FeNO concentration is reduced below the subject's pre-administration FeNO concentration.

[0194] In another embodiment, the subject's FeNO level is reduced by at least about 20%. In yet another embodiment, the subject's FeNO level is reduced by at least about 30%. In yet another embodiment, the subject's FeNO level is reduced by at least about 40%. In one embodiment, the subject's FeNO level is reduced by at least about 50%. In another embodiment, the subject's FeNO level is reduced by at least about 60%. In yet another embodiment, the subject's FeNO level is reduced by at least about 65%. In another embodiment, the subject's FeNO level is reduced by at least about 70%. In yet another embodiment, the subject's FeNO level is reduced by at least about 75%. In yet another embodiment, the subject's FeNO level is reduced by at least about 80%. In one embodiment, the subject's FeNO level is reduced below the subject's pre-administration FeNO level and below the FeNO level during placebo treatment.

[0195] In another embodiment, the formulation further comprises lactose and magnesium stearate.In yet another embodiment, the formulation is administered in a single capsule.

[0196] Preparation method Formulations containing Compound I were found to contain large aggregates upon visual inspection. Notably, formulations prepared by blending the lactose:MgSt premix with the API:MgSt premix without an intermediate co-milling step resulted in greater variability in content uniformity (i.e., lower levels of uniformity) and lower assayed drug concentrations. In contrast, formulations prepared with an intermediate co-milling step, i.e., co-milling the lactose:MgSt premix and API:MgSt premix prior to blending, exhibited improved content uniformity. This suggests that an additional co-milling step may be necessary to blend the formulation components to produce formulations containing Compound I suitable for clinical trials.

[0197] In one aspect, provided herein is a method for preparing a dry powder pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I), the method comprising: (a) co-milling (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile with magnesium stearate to prepare a first pre-blend; (b) co-milling magnesium stearate and lactose to prepare a second pre-blend; (c) mixing the first pre-mix and the second pre-mix together to prepare the formulation.

[0198] In some embodiments, a portion of the second pre-mixture is used to coat the co-mill before co-milling the first pre-mixture, hi some embodiments, a portion of the second pre-mixture is mixed with the first pre-mixture before co-milling the first pre-mixture.

[0199] In some embodiments, the method comprises co-milling a pre-blend of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate, wherein the pre-blend is 4.0 to 14.0% by weight magnesium stearate.

[0200] In some embodiments, the method comprises co-milling a pre-blend of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate, wherein the pre-blend is 4.0 to 8.0% by weight magnesium stearate.

[0201] In some embodiments, the method comprises co-milling a pre-blend of lactose and magnesium stearate, wherein the pre-blend is 0.4-1.1% magnesium stearate by weight.

[0202] In some embodiments, the method comprises co-milling a pre-blend of lactose and magnesium stearate, wherein the pre-blend is 0.8-1.1% magnesium stearate by weight.

[0203] In some embodiments, the method comprises performing step (c) with high shear mixing.

[0204] In some embodiments, the method comprises performing step (c) by TRV mixing.

[0205] In some embodiments, the formulation is enclosed in a capsule or blister.

[0206] In some embodiments, the formulation is encapsulated.

[0207] Additionally, formulations containing Compound I were found to electrostatically adhere to plastic powder handling materials. Specifically, when the formulations were transferred from plastic transfer bags, visual inspection revealed that a significant amount of bulk powder adhered to the interior walls of the transfer bags. Electrostatic adhesion resulted in formulations with significant variability in drug content measurements and less-than-optimal content uniformity. Electrostatic adhesion was reduced by replacing the plastic transfer bags with clean GMP stainless steel containers and incorporating a settling period (e.g., 10-120 hours) into the formulation process before any substantial handling or processing. Thus, formulations prepared using clean GMP stainless steel containers and with a settling period before testing consistently exhibited increased drug content and improved content uniformity.

[0208] In another aspect, provided herein is a method for preparing a dry powder pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I), the method comprising: (a) mixing (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile with magnesium stearate to prepare a first premix; (b) mixing magnesium stearate and lactose to prepare a second preblend; (c) mixing the first pre-mix and the second pre-mix together to prepare a formulation; (d) allowing the formulation to stand.

[0209] In yet another aspect, provided herein is a method for preparing a dry powder pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I), the method comprising: (a) mixing (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile with magnesium stearate to prepare a first premix; (b) mixing magnesium stearate and lactose to prepare a second preblend; (c) mixing the first pre-mix and the second pre-mix together to prepare a formulation; (d) allowing the formulation to stand for 10 to 120 hours.

[0210] In some embodiments, the method includes a standing step (d) of 15 to 65 hours.

[0211] In some embodiments, after the resting period, the formulation is further processed, which may include, but is not limited to, additional processing, additional formulation steps, or any other operations necessary to prepare the formulation for administration to a subject.

[0212] In some embodiments, the method includes preparing a premix of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate, wherein the premix is ​​4.0 to 14.0% by weight magnesium stearate.

[0213] In some embodiments, the method includes preparing a premix of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate, wherein the premix is ​​4.0 to 8.0% by weight magnesium stearate.

[0214] In some embodiments, the method includes preparing a pre-blend of lactose and magnesium stearate, wherein the pre-blend is 0.4 to 1.1% magnesium stearate by weight.

[0215] In some embodiments, the method includes preparing a pre-blend of lactose and magnesium stearate, wherein the pre-blend is 0.8-1.1% magnesium stearate by weight.

[0216] In one embodiment, a first pre-mix is ​​prepared in a container and a second pre-mix is ​​prepared in another container, and then the pre-mixes are mixed. The pre-mixes can be prepared in separate containers prior to step (c).

[0217] In some embodiments, the method comprises performing step (c) with high shear mixing.

[0218] In some embodiments, the method comprises performing step (c) by TRV mixing.

[0219] In some embodiments, the method comprises: (e) The method includes the additional step of filling the formulation into capsules.

[0220] In some embodiments, the method comprises: (e) The method includes the additional step of filling the blisters with the formulation.

[0221] In some embodiments, the method is performed without the use of plastic powder handling materials.

[0222] In some embodiments, the method is performed without the use of plastic powder handling materials, including plastic spatulas, plastic scoops, and plastic transfer bags.

[0223] In some embodiments, the method is performed without the use of a plastic transfer bag, including a ChargeBag®.

[0224] In some embodiments, the method is carried out using powder handling materials made from stainless steel.

[0225] In some embodiments, the method is carried out using stainless steel powder handling materials, including stainless steel spatulas, stainless steel scoops, stainless steel funnels, and stainless steel containers.

[0226] Formulations of the present disclosure can be prepared by combining any of the above concepts (i.e., replacing plastic powder handling materials with stainless steel powder handling materials to reduce electrostatic adhesion, incorporating a settling period (10-120 hours) to reduce electrostatic adhesion, and incorporating an intermediate co-grinding step to reduce aggregate size).

[0227] In one aspect, provided herein is a method for preparing a dry powder pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile, the method comprising: (a) mixing (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I) or a pharmaceutically acceptable salt thereof with magnesium stearate to prepare a first premix; (b) mixing magnesium stearate and lactose to prepare a second preblend; (c) mixing the first pre-mix and the second pre-mix together to prepare a formulation; (d) allowing the formulation to stand for 10 to 120 hours.

[0228] In some embodiments, the standing step (d) is for 15 to 65 hours.

[0229] The formulation is allowed to rest before any further significant processing or processing, which may include, but is not limited to, additional formulation steps or any other operations necessary to prepare the formulation for administration to a subject.

[0230] In some embodiments, the method includes co-grinding the first pre-mixture and the second pre-mixture prior to step (c).

[0231] In some embodiments, prior to co-milling the first pre-mixture and the second pre-mixture, a portion of the second pre-mixture is used to coat the co-mill.

[0232] In some embodiments, the method comprises co-milling a pre-blend of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate, wherein the pre-blend is 4.0 to 14.0% by weight magnesium stearate.

[0233] In some embodiments, the method comprises co-milling a pre-blend of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate, wherein the pre-blend is 4.0 to 8.0% by weight magnesium stearate.

[0234] In some embodiments, the method comprises co-milling a pre-blend of lactose and magnesium stearate, wherein the pre-blend is 0.4-1.1% magnesium stearate by weight.

[0235] In some embodiments, the method comprises co-milling a pre-blend of lactose and magnesium stearate, wherein the pre-blend is 0.8-1.1% magnesium stearate by weight.

[0236] In one embodiment, a first pre-mix is ​​prepared in a container and a second pre-mix is ​​prepared in another container, and then the pre-mixes are mixed. The pre-mixes can be prepared in separate containers prior to step (c).

[0237] In some embodiments, the method comprises performing step (c) with high shear mixing.

[0238] In some embodiments, the method comprises performing step (c) by TRV mixing.

[0239] In some embodiments, the method comprises: (e) The method includes the additional step of filling the formulation into capsules.

[0240] In some embodiments, the method comprises: (e) The method includes the additional step of filling the blisters with the formulation.

[0241] In one aspect, provided herein is a method for preparing a dry powder pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I), the method comprising: (a) co-milling (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I) or a pharmaceutically acceptable salt thereof with magnesium stearate to prepare a first premix; (b) co-milling magnesium stearate and lactose to prepare a second pre-blend; (c) mixing the first pre-mix and the second pre-mix together to prepare the formulation.

[0242] In some embodiments, a portion of the second pre-mixture is used to coat the co-mill before co-milling the first pre-mixture, hi some embodiments, a portion of the second pre-mixture is mixed with the first pre-mixture before co-milling the first pre-mixture.

[0243] In some embodiments, the method comprises co-milling a pre-blend of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate, wherein the pre-blend is 4.0 to 14.0% by weight magnesium stearate.

[0244] In some embodiments, the method comprises co-milling a pre-blend of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate, wherein the pre-blend is 4.0 to 8.0% by weight magnesium stearate.

[0245] In some embodiments, the method comprises co-milling a pre-blend of lactose and magnesium stearate, wherein the pre-blend is 0.4-1.1% magnesium stearate by weight.

[0246] In some embodiments, the method comprises co-milling a pre-blend of lactose and magnesium stearate, wherein the pre-blend is 0.8-1.1% magnesium stearate by weight.

[0247] In some embodiments, the method comprises: (d) An additional step of allowing the formulation to stand for 10 to 120 hours.

[0248] In some embodiments, the method comprises: (d) An additional step of allowing the formulation to stand for 15 to 65 hours.

[0249] In some embodiments, the method comprises performing step (c) with high shear mixing.

[0250] In some embodiments, the method comprises performing step (c) by TRV mixing.

[0251] In some embodiments, the method comprises: (e) The method includes the additional step of filling the formulation into capsules.

[0252] In some embodiments, the method comprises: (e) The method includes the additional step of filling the blisters with the formulation.

[0253] In yet another aspect, provided herein is a method for preparing a dry powder pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I), the method comprising: (a) mixing (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I) or a pharmaceutically acceptable salt thereof with magnesium stearate to prepare a first premix; (b) mixing magnesium stearate and lactose to prepare a second preblend; (c) mixing the first pre-mix with the second pre-mix; (d) co-grinding the product prepared in step (c); (e) mixing the products prepared in step (d) to prepare a formulation.

[0254] In some embodiments, a portion of the second pre-mixture is co-milled prior to step (c).

[0255] In some embodiments, the first pre-mixture has 4.0 to 14.0 wt % magnesium stearate.

[0256] In some embodiments, the first pre-mixture has 4.0 to 8.0% by weight magnesium stearate.

[0257] In some embodiments, the second pre-blend has 0.4 to 1.1 wt % magnesium stearate.

[0258] In some embodiments, the second pre-blend has 0.8 to 1.1% by weight magnesium stearate.

[0259] In some embodiments, the method comprises: (f) An additional step of allowing the formulation to stand for 10 to 120 hours.

[0260] In some embodiments, the method comprises: (f) An additional step of allowing the formulation to stand for 15 to 65 hours.

[0261] In some embodiments, the method includes performing step (e) with high shear mixing.

[0262] In some embodiments, the method includes performing step (e) by TRV mixing.

[0263] In some embodiments, the method comprises: (g) The method includes the additional step of filling the formulation into capsules.

[0264] In some embodiments, the method comprises: (h) The method includes the additional step of filling the blisters with the formulation.

[0265] In one embodiment, after the resting period, the formulation is further processed, which may include, but is not limited to, additional formulation steps or any other operations necessary to prepare the formulation for administration to a subject.

[0266] In some embodiments, the method is performed without the use of plastic powder handling materials.

[0267] In some embodiments, the method is performed without the use of plastic powder handling materials, including plastic spatulas, plastic scoops, and plastic transfer bags.

[0268] In some embodiments, the method is performed without the use of a plastic transfer bag, including a ChargeBag®.

[0269] In some embodiments, the method is carried out using powder handling materials made from stainless steel.

[0270] In some embodiments, the method is carried out using stainless steel powder handling materials, including stainless steel spatulas, stainless steel scoops, stainless steel funnels, and stainless steel containers.

[0271] The drug particles or pharmaceutically active agent particles (also referred to herein as "active particles") in the formulations of the present disclosure must be aerosolized into ultrafine aerosols (see above) so that they can be delivered to the appropriate target area in the lungs. Typically, for pulmonary deposition, the active particles have a diameter of less than 10 μm, often 0.1-7 μm, 0.1-5 μm, or 0.5-5 μm.

[0272] For a formulation to reach the deep lungs or bloodstream via inhalation, the active agent in the formulation must be in the form of very fine particles, e.g., with a mass median aerodynamic diameter (MMAD) of less than 10 μm. It is well recognized that particles with an MMAD greater than 10 μm are likely to impact the pharyngeal wall and typically do not reach the lungs. Particles with an MMAD in the 5-2 μm range generally deposit in the respiratory bronchioles, whereas particles with an MMAD in the 3-0.05 μm range are more likely to deposit in the respiratory bronchioles and alveoli, potentially providing benefits to the inflammation of the narrow airways seen in respiratory diseases, including asthma and COPD.

[0273] When dry powders are produced using conventional processes, the active particles vary in size, and in many cases, this variation can be significant. This can make it difficult to ensure a sufficiently high percentage of the active particles are the appropriate size for administration to the correct site. Therefore, it is desirable to have a dry powder formulation with as narrow a size distribution of the active particles as possible. This improves dose efficiency and reproducibility. Fine particles, i.e., particles with an MMAD of less than 5 μm and smaller, tend to become increasingly thermodynamically unstable as their surface area-to-volume ratio increases. This leads to an increase in surface free energy with decreasing particle size, resulting in an increased tendency for particles to agglomerate. The aggregation of fine particles and their adhesion to the walls of the inhaler can result in the particles exiting the inhaler as large, stable agglomerates, or they may be unable to exit the inhaler and remain attached to the interior of the inhaler, or they may further clog or block the inhaler.

[0274] The uncertainty in the extent to which stable particle agglomerates form between inhaler actuations, and even between different inhalers and different batches of particles, leads to poor dose reproducibility. Furthermore, agglomerate formation means that the MMAD of the active particles can increase significantly, preventing active particle agglomerates from reaching the required parts of the lung.

[0275] These micron to submicron particle sizes required for deep lung delivery lead to the problem that the inhalable active particles tend to be highly cohesive, meaning that the particles generally have poor flowability and aerosolize poorly.

[0276] To improve the properties of powder formulations, particularly the flowability and dispersibility of the formulation, dry powder formulations often contain additives intended to reduce agglomeration between fine particles in the dry powder formulation. The additives are thought to disrupt the weak binding forces between small particles, helping them to remain separated and reducing adhesion of such particles to each other, to other particles in the formulation (if present), and to the interior surfaces of the inhaler. If particle agglomerates form, the addition of additive particles reduces the stability of those agglomerates, making them more likely to break up in the turbulent airflow created during inhaler actuation when the particles are expelled from the inhaler and inhaled.

[0277] The compositions described herein may include additive substances (eg, in the form of discrete particles of a size comparable to that of the active particulates).

[0278] The additive may be an anti-adhesion material, which reduces inter-particle cohesion and further prevents fine particles from adhering to surfaces within the inhaler. The additive is advantageously an anti-friction agent or glidant, which improves the flow characteristics of the powder formulation within the inhaler. Additives used in this manner are not necessarily usually called anti-adhesion agents or anti-friction agents, but they have the effect of reducing inter-particle cohesion or improving powder flow. Therefore, additives are sometimes called force control agents (FCAs), and such additives typically result in better dose reproducibility and a higher fine particle fraction (FPF).

[0279] Thus, as used herein, additive substance or FCA refers to a substance whose presence on the surface of a particle can alter the surface adhesive and cohesive forces experienced by that particle in the presence of other particles and relative to the exposed surface of the particle. Generally, its function is to reduce both adhesive and cohesive forces.

[0280] Reducing the tendency of particles to bond strongly either to one another or to the device itself not only reduces powder clumping and adhesion, but also promotes improved flow characteristics. This reduces variability in the amount of powder metered for each dose and improves release of the powder from the device, thereby increasing dose reproducibility. It also increases the likelihood that the active agent exiting the device will reach the subject's lower lungs.

[0281] The use of such additive substances is disclosed, for example, in WO1996 / 023485 and WO1997 / 003649.

[0282] It is also known that micronized drug particles and additive substances may be vigorously co-milled to produce composite particles. As disclosed in a prior patent application published as WO2002 / 043701, this co-milling can improve dispersibility. Furthermore, a prior patent application published as WO2002 / 000197 discloses that fine particles of an excipient substance can be vigorously co-milled with an additive substance to prepare composite excipient particles, to which active fine particles and, optionally, coarse carrier particles can be added. This has also been shown to improve dispersibility.

[0283] At least two methods for processing active and additive particles can be used in the present disclosure. First, there are compression-type processes, such as Mechanofusion and Cyclomix, and related methods, such as Hybridizer or Nobilta. As the name suggests, Mechanofusion is a dry coating process designed to mechanically fuse a first material onto a second material. The first material is generally smaller and / or softer than the second material. The principles behind the Mechanofusion and Cyclomix processes differ from those of other comminution technologies in that they involve a special interaction between the internal elements and the container wall and are based on the supply of energy through controlled, substantial compression forces.

[0284] The active and additive particles are fed into a mechanofusion-driven vessel (e.g., Mechanofusion System (Hosokawa Micron Corporation)), where they are centrifugal-forced against the vessel's inner wall. The inner wall and the curved inner element together form a gap, or nip, where the particles are pressed against each other. The powder is compressed between the fixed gap in the drum wall and the curved inner element due to the high relative velocity between the drum and the element. As a result, the particles are subjected to very high shear forces and very strong compressive stresses while trapped between the inner drum wall and the inner element (which has a greater curvature than the inner drum wall). The particles are locally heated, softened, broken, deformed, flattened, and pressed against each other with enough energy to coat the additive particles around the active particles and form a coating. The energy is generally sufficient to break down agglomerates, and some size reduction of both components may occur. While the coating may not be complete, the deagglomeration of the particles during the process ensures that the coating is substantially complete and may cover a large portion of the particle's surface.

[0285] Such Mechanofusion and Cyclomix processes achieve effective mixing and application of additives to the surfaces of the active particles by applying forces strong enough to separate individual particles of the active material and to break up tightly bound agglomerates of the active particles.

[0286] A particularly desirable aspect of the described processing method is that the additive material is deformed during mechanofusion and can be applied or fused to the surface of the active particles. In reality, however, this compression process results in little or no reduction in drug particle size, especially when the drug particles are already in micronized form (i.e., less than 10 μm). The only physical change that can be observed is plastic deformation of the particles to a more rounded shape.

[0287] Further processing techniques include those described by R. Pfeffer et al., "Synthesis of engineered particulates with tailored properties using dg particle coating," Powder Technology 117 (2001) 40-67. Such techniques include processes using a Mechanofusion machine, a Hibidizer machine, a Theta Composer, a magnetically assisted impaction process, and a rotating fluidized bed coater. The Cyclomix process can also be used.

[0288] This technique involves compressing a mixture of particles of dispersion and particles of a pharmaceutically active agent in a nip formed between two parts of a machine that can be used to provide the necessary mechanical energy (as in Mechanofusion and Cyclomix devices). Several processing methods are described below.

[0289] Mechanofusion: This dry coating method is designed to mechanically fuse a first material onto a second material, which is generally smaller and / or softer than the second material. The principle of Mechanofusion and Cyclomix processing differs from other processing techniques in that it involves a special interaction between the internal elements and the container wall, and is based on the delivery of energy through controlled, substantial compressive forces.

[0290] The active fine particles and dispersant particles are fed into a mechanofusion-driven vessel, where they are centrifugal-forced against the vessel's inner wall. The powder is compressed between a fixed gap in the drum wall and a curved internal element due to the high relative velocity between the drum and the element. The internal wall and the curved element together form a gap or nip where the particles are pressed against each other. As a result, the particles are subjected to very high shear forces and very strong compressive stresses while trapped between the drum's inner wall and the internal element (which has a greater curvature than the drum's inner wall). The particles are locally heated, softened, broken, deformed, flattened, and collide violently with each other with enough energy to form a coating of dispersant particles around the core particles. The energy is generally sufficient to break down agglomerates, and some size reduction of both components may occur. Embedding and fusion of the dispersant additive particles into the active particles may occur, which may be facilitated by the relative differences in hardness (and possibly size) of the two components. Either the outer vessel or the inner element can rotate to provide relative motion. The gap between their surfaces is relatively small, typically less than 10 mm, and can be less than 5 mm or even less than 3 mm. This gap is fixed, resulting in better control of the compression energy than is achieved with some other forms of milling, such as ball mills and media mills. Furthermore, the lack of influence of the grinding media surface generally minimizes wear and resulting contamination. Rotation speeds can range from 200 to 10,000 rpm. A scraper may be present to break up any stuck material that accumulates on the vessel surface. This is particularly advantageous when using fine, sticky starting materials. Local temperature can be controlled using heating / cooling devices integrated into the drum vessel wall. The powder may be recirculated through the vessel.

[0291] Cyclomix method (Hosokawa Micron): The Cyclomix consists of a stationary conical vessel with a high-speed rotating shaft and paddles that move close to the wall. The high rotational speed of the paddles propels the powder toward the wall, resulting in the mixture being subjected to very high shear and compressive forces between the wall and the paddle. This effect, similar to that in mechanofusion described above, can be sufficient to locally heat, soften, break, deform, flatten, and coat particles of dispersant around the active particles to form a coating. The energy is sufficient to break down agglomerates and, depending on the conditions and the size and nature of the particles, can also result in some size reduction of both components.

[0292] Hybridizer method: This is a dry process that can be described as embedding or filming one powder onto another. Active particles and fine or ultrafine particles of dispersant are fed into a conventional high-shear mixer premixing system to form a coherent mixture. This powder is then fed into a hybridizer. The powder is impacted by the blades of a high-speed rotor within a stationary container, where it undergoes ultra-high-speed impact, compression, and shear, and is then recirculated within the container. The active and additive particles collide with each other. Typical rotation speeds are in the range of 5,000 to 20,000 rpm. The relatively flexible dispersant particles are subjected to sufficient impact force to soften, break, deform, flatten, and form a coating around the active particles. Some embedding into the surface of the active particles may also occur.

[0293] A second type of process mentioned in the prior art is impact milling processes, such as ball milling, jet milling, and the use of homogenizers.

[0294] Ball milling is the milling method used in many of the prior art processing methods. Centrifugal ball milling and planetary ball milling can be used.

[0295] Jet mills are capable of reducing solids to particle sizes in the low micron to submicron range. The milling energy is provided by a gas stream from horizontal milling air nozzles. Particles in the fluidized bed created by the gas stream are accelerated toward the center of the mill where they collide with slower-moving particles. The gas stream and the particles carried within it create intense turbulence, and as the particles collide with each other, they are milled.

[0296] In a high-pressure homogenizer, the particle-laden fluid is forced through a valve at high pressure, creating high shear and turbulent conditions. Suitable homogenizers include the EmulsiFlex high-pressure homogenizer, which is capable of pressures up to 4000 bar, the Niro Soavi high-pressure homogenizer (capable of pressures up to 2000 bar), and the Microfluidics Microfluidizer (maximum pressure 2750 bar).

[0297] Alternatively, the milling can use a high energy media mill or an agitator bead mill, such as a Netzsch high energy media mill or a DYNO mill (Willy A. Bachofen AG, Switzerland).

[0298] All of these processes produce high energy impacts between the media and the particles or between the particles themselves. In practice, these processes are good for preparing very small particles, but it has been found that ball mills, jet mills, and homogenizers are not as effective as compaction-type processes in providing improved dispersion of the resulting drug powder. The impact processes described above are believed to be less effective than compaction-type processes in producing a coating of additive material on each particle.

[0299] For purposes of this disclosure, all forms of co-milling are encompassed, including methods similar to or related to all of the methods described above. For example, methods similar to mechanofusion are encompassed, such as those utilizing one or more ultra-high shear rotors (i.e., 2000-50,000 rpm) in which blades or other elements sweep across the interior surface of a vessel having a small gap (i.e., 0.1 mm-20 mm) between the wall and the blade. Also encompassed are conventional methods (such as those described in WO 2002 / 043701) involving co-milling an active material with an additive material. These methods result in composite active particles containing ultrafine active particles bearing a certain amount of additive material on their surface.

[0300] In the past, jet milling was considered an unattractive method for micronizing active and additive particles in the preparation of powder formulations to be dispensed using passive devices: Collisions between particles in a jet mill are somewhat uncontrolled, and therefore, those skilled in the art believed that this technique was unlikely to impart the desired coating of additive material to the surface of the active particles.

[0301] Furthermore, unlike the situation with compression-type processes such as Mechanofusion and Cyclomixing, it was believed that jet milling could result in segregation of the powder components, with the result that the finer particles that would be most effective could escape the process. In contrast, it is clear how techniques such as Mechanofusion could result in the desired coating.

[0302] Jet milling has been shown to be an attractive process for micronizing active and additive particles, particularly for preparing powder formulations to be used in active devices (see the disclosure of the prior patent application published as WO 2004 / 001628, which is incorporated herein by reference in its entirety). In another embodiment, the additive material may be in the form of particles that adhere to the surfaces of the active and carrier particles. Such additive material may be fused to the surfaces of the active and carrier particles.

[0303] The carrier particles can be any acceptable inert excipient material or combination of materials. For example, carrier particles frequently used in the prior art can be composed of one or more materials selected from sugar alcohols, polyols, and crystalline sugars. Other suitable carriers include inorganic salts such as sodium chloride and calcium carbonate, organic salts such as sodium lactate, and other organic compounds such as polysaccharides and oligosaccharides. Advantageously, the carrier particles include polyols. In particular, the carrier particles can be particles of crystalline sugars, such as mannitol, dextrose, or lactose. In some embodiments, the carrier particles are trehalose particles. The carrier particles can be composed of lactose.

[0304] The additive may comprise a metal stearate or a derivative thereof, such as sodium stearyl fumarate or sodium stearyl lactate. Advantageously, the additive comprises a metal stearate, such as zinc stearate, magnesium stearate, calcium stearate, sodium stearate, or lithium stearate. The additive may comprise magnesium stearate, such as vegetable magnesium stearate, or any form of commercially available metal stearate, which may be of vegetable or animal origin and may also contain other fatty acid components, such as palmitate or oleate.

[0305] Products and Kits The formulations described herein can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Thus, an article of manufacture, such as a container, containing a pharmaceutical formulation described herein and a label containing instructions for use of the composition is also contemplated.

[0306] In some embodiments, the article of manufacture is a container containing a pharmaceutical formulation described herein. In some embodiments of the articles of manufacture described herein, the formulation is encapsulated.

[0307] Kits are also contemplated.For example, the kit can include the pharmaceutical formulation of the present disclosure and a package insert containing instructions for using the composition to treat disease.In some embodiments, the kit includes multiple formulations described herein, each containing a therapeutically effective amount of Compound I, and instructions for administering them to a person in need thereof.

[0308] Equivalents and Scope While various disclosed embodiments have been particularly shown and described in this disclosure, it will be apparent to those skilled in the art that various changes in form and details can be made therein without departing from the spirit and scope of the embodiments disclosed herein and set forth in the appended claims.

[0309] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, equivalents to the specific embodiments described herein. The scope of the present disclosure is not intended to be limited to the above Description, but rather is as set forth in the appended claims.

[0310] Where ranges are specified, their endpoints are inclusive. Furthermore, it will be apparent that, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can, in various embodiments of the present disclosure, take any specific value or subrange within the stated range, down to one-tenth of the unit of the lower limit of the range, unless otherwise clearly indicated by context.

[0311] Furthermore, it is clear that if a particular embodiment of the present invention falls within the scope of the prior art, it may be explicitly excluded from any one or more of the claims. Such an embodiment may be excluded even if the exclusion is not explicitly stated herein, since it is considered to be known to those skilled in the art. Any particular embodiment of the compositions disclosed herein may be excluded from any one or more of the claims for any reason, regardless of whether it is related to the existence of prior art.

[0312] All sources, including references, publications, databases, database entries, and techniques cited herein, are incorporated herein by reference, even if the citation is not explicitly stated. In the event of a conflict between the source and this application, the disclosure in this application shall control. [Example]

[0313] Compound I, (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile, can be prepared according to the procedures outlined in WO2011 / 051452 (see Example 7i) and WO2016 / 124464 (Form II, see Example 2.2), both of which are incorporated herein by reference in their entireties. All references to Compound I of the present disclosure in the Examples refer to polymorphic Form II.

[0314] The abbreviations used herein have the following meanings: [Table 2-1] [Table 2-2]

[0315] General Procedure for Drug Content Determination All drug content measurements were performed using position 7 as shown in FIG.

[0316] 1 wt% Compound I formulation Approximately 300 mg of the compound I-containing formulation was transferred into a vial. The sample was transferred into a 500 mL flask and diluted to approximately 6 mcg / mL. Approximately 200 mL of the diluted solution was then sonicated for 10 minutes. The content of compound I in the diluted sample was then measured by HPLC.

[0317] Formulation of 10 wt% Compound I Approximately 400 mg of a formulation containing Compound I was transferred into a vial. The sample was transferred into a 500 mL flask and diluted to approximately 80 mcg / mL. Approximately 200 mL of the diluted solution was then sonicated for 10 minutes. Approximately 20 mL of the sonicated diluted solution was transferred into a 100 mL flask and diluted to a concentration of approximately 16 mcg / mL. The content of Compound I in the diluted sample was then measured by HPLC.

[0318] General Procedure for Content Uniformity Determination All content uniformity measurements were performed using positions 1-10 as shown in Figure 1 .

[0319] 1 wt% Compound I formulation Approximately 60 mg of a formulation containing Compound I was transferred to a vial. The sample was transferred to a 100 mL flask and diluted to approximately 6 mcg / mL. Approximately 50 mL of the diluted solution was then sonicated for 10-20 minutes. The content uniformity of Compound I in the diluted sample was then determined by HPLC. This process was repeated for a total of 10 samples.

[0320] Formulation of 10 wt% Compound I Approximately 120 mg of a formulation containing Compound I was transferred to a vial. The sample was transferred to a 500 mL flask and diluted to approximately 24 mcg / mL. Approximately 250 mL of the diluted solution was then sonicated for 10-20 minutes. The content uniformity of Compound I in the diluted sample was then determined by HPLC. This process was repeated for a total of 10 samples.

[0321] General Procedure for Measuring APSD, MMAD, FPM, and FPF Preparation of cup coating agent The cup coating was prepared by mixing 150 mL of a mixture of Brij® 35, ethanol, and glycerol with 850 mL of ethanol.

[0322] NGI Procedure The cup coating agent was prepared, and the NGI was assembled. The collection cup was then coated with the cup coating agent and then allowed to dry. A PALL® A / E 76 mm filter was placed inside the backup filter and attached to the NGI. Approximately 15 mL of diluent was added to the pre-separator insert. The flow rate was set to 90 L / min, and the capsule was punctured. A single dose was released into the NGI by activating the time-controlled solenoid valve for 2.70 seconds. Sample diluent was added (10 mL for the 0.2 mg and 2.0 mg doses, and 20 mL for the 4.0 mg dose), and the collection cup was agitated on an NGI Gentle Rocker for 10 minutes. 40 mL of sample diluent was added to the induction port and shaken for 1 minute. 50 mL of sample diluent was added to the pre-separator and shaken for 1 minute. The backup filter was transferred to a crystallizing dish containing 20 mL of sample diluent and then sonicated for 5 minutes. The capsules from each run were then transferred to a 20 mL flask and sample diluent was added. The suspension was then shaken and sonicated until completely dissolved. The resulting solution was allowed to equilibrate under ambient conditions and then brought to volume. Each single dose of RS01 was placed in an individual plastic bag and 20 mL of recovery solution was added. The bag was shaken by hand for 1 minute and filtered prior to HPLC analysis.

[0323] General Procedure for Measuring the Delivered Dose of Compound I A castellated fixed volume dose unit sampling apparatus (DUSA) was assembled and attached to a backup filter. The DUSA used PALL® A / E 47 mm filter paper, and the backup filter used a PALL® A / E 76 mm filter. The solenoid timer was then primed and the flow rate adjusted to 90 L / min. The pre-sample weight of the device was recorded, and the inhaler was activated. Two doses were released into the DUSA by activating the time-controlled solenoid valve. The post-sample weight of the device was then recorded, and the exhaust bung was inserted into the exhaust port. Sample diluent (50 mL) was introduced into the DUSA through the mouthpiece adapter, and the DUSA was placed on an orbital shaker at 250 shakes per minute for 5 minutes. The capsule was dissolved in the diluent, and the drug retained in the device was recovered by washing with the diluent. Dilutions were performed using 4 mg capsules. All samples were filtered through disposable 0.2 μm PTFE syringeless filters with polypropylene housings into HPLC vials and analyzed by HPLC.

[0324] Example 1: Formulations containing Compound I Mixture 1 (2 kg scale) A 1 wt% magnesium stearate excipient preblend, i.e., lactose:MgSt, was prepared by blending 10% fines (3961.3 g) with magnesium stearate (38.8 g). An 88.0 wt% magnesium stearate API preblend (12.0 wt% magnesium stearate), i.e., API:MgSt, was prepared by blending Compound I (35.4 g) with magnesium stearate (4.8 g). Approximately 1977.1 g of the lactose:MgSt preblend was blended with 22.8 g of the API:MgSt preblend. The resulting mixture was then homogenized in a TRV blender at 500 rpm for 14 minutes to yield a 1.0 wt% API bulk powder formulation (Mix 1). Prior to testing, Mix 1 bulk powder was transferred to a plastic ChargeBag®.

[0325] The content uniformity and drug content measured for the bulk powder of Blend 1 are shown in Table 1.

[0326] [Table 3]

[0327] mixture 1a To investigate the effect of static charge on bulk drug content and content uniformity, Blend 1 was reprocessed in a stainless steel container according to the following procedure: During transfer to the stainless steel container, large agglomerates of Blend 1 were observed, suggesting the need for an additional co-milling step in the manufacture of Compound I formulations.

[0328] The Blend 1 bulk powder was transferred to a clean, hermetically sealed GMP stainless steel container (160 mm x 160 mm) and reprocessed by co-milling at 1000 rpm. The mixture was then homogenized by TRV mixing at 1000 rpm for 7 minutes to yield the formulation (Blend 1a). The content uniformity and drug content measured for Blend 1a are shown in Table 2. These data indicate that the co-milling step in the manufacture of Blend 1a improved the content uniformity. However, the drug content of Blend 1a remained low.

[0329] [Table 4]

[0330] Example 2: Low-dose formulation of Compound I (0.2 mg) To further investigate the effect of static charge within the formulation of Compound I, a rest period was introduced into the manufacturing process according to the following procedure: Additionally, the magnesium stearate content in the API:MgSt preblend was reduced to investigate its potential impact on the formulation of Compound I.

[0331] Mixture 2a (with co-grinding) (0.4 kg scale) A 0.9 wt% magnesium stearate excipient preblend, i.e., lactose:MgSt, was prepared by blending 10% fines (3962.4 g) of lactose with 37.6 g of magnesium stearate. A 6.5 wt% magnesium stearate API preblend, i.e., API:MgSt, was prepared by blending Compound I (69.9 g) with 4.9 g of magnesium stearate. In a subsequent step, 395.1 g of lactose:MgSt preblend and 4.8 g of API:MgSt preblend were processed into a 1 L TRV bowl using a U5 Comil® equipped with a 457 mcm sieve at 1000 rpm. The resulting mixture was then homogenized in a TRV blender at 1209 rpm for 4 minutes to yield a 1 wt% API bulk powder formulation (Mixture 2a). The blend 2a bulk powder was transferred to a clean, sealed GMP stainless steel container (160 mm x 160 mm), followed by a rest period (20, 40, or 60 hours) before capsule filling. For a target dose of 0.2 mg, 20 mg of blend 2a bulk powder was manually filled into capsules.

[0332] The composition of the resulting 0.2 mg product is shown in Table 3.

[0333] [Table 5]

[0334] The content uniformity and drug content measured for the Blend 2a bulk powder are shown in Table 4, along with the aerodynamic particle size distribution measured for the Blend 2a capsules.

[0335] Mixture 2b (without co-milling) (0.4 kg scale) A 0.9 wt% magnesium stearate excipient preblend, i.e., lactose:MgSt, was prepared by blending lactose (10% fines (3962.4 g)) with magnesium stearate (37.6 g). A 6.5 wt% magnesium stearate API preblend, i.e., API:MgSt, was prepared by blending Compound I (69.9 g) with magnesium stearate (4.9 g). Approximately 395.3 g of the lactose:MgSt preblend was blended with 4.8 g of the API:MgSt preblend. The resulting mixture was then homogenized in a TRV blender at 1209 rpm for 4 minutes to yield a 1 wt% API bulk powder formulation (Mix 2b). The Mix 2b bulk powder was transferred to a clean, sealed GMP stainless steel container (160 mm x 160 mm) followed by a rest period (20, 40, or 60 hours) before capsule filling. For a target dose of 0.2 mg, 20 mg of blend 2b bulk powder was hand-filled into capsules.

[0336] The content uniformity and drug content measured for Blend 2b bulk powder are shown in Table 4, along with the aerodynamic particle size distribution measured for Blend 2b capsules. A comparison of the standard deviations for Blend 2a (co-milled) and Blend 2b (no co-milling) from the individual stage profiles of the aerodynamic particle size distribution is shown in Table 5.

[0337] [Table 6]

[0338] As can be seen in Table 4, there was a decrease in variability in content uniformity of Blend 2b bulk powder after the 60-hour settling period compared to the 20-hour and 40-hour settling periods, as evidenced by the decrease in RSD. Furthermore, the use of a co-milling process in the manufacture of formulations containing Compound I resulted in higher drug delivery efficiencies, as estimated by the average FPF. Also, compared to Table 1, the data in Table 4 suggest that the use of stainless steel equipment, co-milling, settling period, and lower magnesium stearate concentration in the API:MgSt preblend resulted in higher drug loads for formulations containing Compound I.

[0339] [Table 7]

[0340] As shown in Table 5, Mix 2b exhibited less variability in standard deviations from the individual APSD stage profiles after a 60-hour rest period than after a 20-hour or 40-hour rest period. Also shown in Table 5, Mix 2a exhibited less variability after a 40-hour and 60-hour rest period than after a 20-hour rest period. Furthermore, for the 40-hour and 60-hour rest periods, the variability was less for Mix 2a than for Mix 2b.

[0341] Example 3: High dose formulations of Compound I (2.0 mg and 4.0 mg) Mixture 3 (0.4 kg scale) A 0.6 wt% magnesium stearate excipient preblend, i.e., lactose:MgSt, was prepared by blending 6% fines (3976.8 g) with magnesium stearate (23.3 g). A 6.5 wt% magnesium stearate API preblend, i.e., API:MgSt, was prepared by blending Compound I (69.9 g) with magnesium stearate (4.9 g). In a subsequent step, a U5 Comil® equipped with a 457 mcm sieve was used to process 356.0 g of the lactose:MgSt preblend and 44.0 g of the API:MgSt preblend into a 1 L TRV bowl at 1000 rpm to prepare a blend. The resulting blend was then homogenized in a TRV blender at 2392 rpm for 4 minutes to obtain a 10 wt% API bulk powder formulation (Blend 3). The Blend 3 bulk powder was transferred to a clean, sealed GMP stainless steel container (160 mm x 160 mm), followed by a rest period (20 or 60 hours) before capsule filling. Size 3 HPMC capsules were manually filled with 20 mg of Blend 3 bulk powder for a target dose of 2.0 mg, and with 40 mg of Blend 3 bulk powder for a target dose of 4.0 mg. The compositions of the resulting 2.0 mg and 4.0 mg products are shown in Table 6.

[0342] [Table 8]

[0343] The content uniformity, drug content, and aerodynamic particle size distribution measured for the bulk powder, 20 mg capsules, and 40 mg capsules are shown in Table 7. The standard deviations from the individual stage profiles of the aerodynamic particle size distribution for the three capsules of the blend are shown in Table 8.

[0344] [Table 9]

[0345] Improved uniformity of Blend 3 bulk powder was observed after the 60-hour settling period compared to the 20-hour settling period, as evidenced by a decrease in RSD. Furthermore, Blend 3 was filled into both 20 mg capsules (2.0 mg Compound I) and 40 mg capsules (4.0 mg Compound I) and showed an increase in mean fine particle fraction after the 60-hour settling period compared to the 20-hour settling period. In addition, the improved drug content over Blend 1 and Blend 1a (Tables 1 and 2) further supports the need for stainless steel equipment, co-milling, and a settling period to produce suitable formulations of Compound I, and supports the need for a lower concentration of magnesium stearate in the API:MgSt preblend to produce formulations containing Compound I, magnesium stearate, and lactose suitable for clinical trials.

[0346] Thus, the improved uniformity of Blend 3, as inferred from content uniformity (Table 7), and the improved drug content of Blend 3 led to clinical trials of formulations comprising Compound I, lactose, and magnesium stearate. In other words, the methods for preparing dry powder pharmaceutical formulations of Compound I disclosed herein and the pharmaceutical formulations of Compound I, lactose, and magnesium stearate disclosed herein resulted in formulations comprising Compound I that were suitable for clinical trial investigation. Prior to this discovery, clinical studies of previous formulations comprising Compound I, lactose, and magnesium stearate could not be conducted due to both the lack of uniformity of Blend 1, as inferred from low content uniformity, and the low drug content (Table 1).

[0347] [Table 10]

[0348] Table 8 shows that there is less variability (as indicated by the lower standard deviation) from the 60 hour rest period than from the 20 hour rest period for both the 20 mg and 40 mg capsules of Blend 3.

[0349] Mixture 4 (2 kg scale) A 0.6 wt% magnesium stearate excipient preblend, i.e., lactose:MgSt, was prepared by blending 6% fines (3976.6 g) with magnesium stearate (23.2 g). A 6.5 wt% magnesium stearate API preblend, i.e., API:MgSt, was prepared by blending Compound I (243.3 g) with magnesium stearate (16.9 g). In a subsequent step, 1792.3 g of lactose:MgSt preblend and 175.9 g of API:MgSt preblend were processed into a 5 L TRV bowl at 1000 rpm using a U5 Comil® equipped with a 457 mcm sieve to prepare a blend. The resulting blend was then homogenized in a TRV blender at 1385 rpm for 7 minutes to obtain a 10 wt% API bulk powder formulation (Blend 4). The Blend 4 bulk powder was transferred to a clean, sealed GMP stainless steel container (160 mm x 160 mm), followed by a 60-hour rest period before capsule filling. Size 3 HPMC capsules were hand-filled with 20 mg of Blend 4 bulk powder for a target dose of 2.0 mg and with 40 mg of Blend 4 bulk powder for a target dose of 4.0 mg.

[0350] The compositions of the resulting 2.0 mg and 4.0 mg products are shown in Table 9.

[0351] [Table 11]

[0352] Content uniformity and drug content are shown in Table 10. Fine particle mass, fine particle fraction, and mass median aerodynamic diameter measured for the 2 mg and 4 mg capsules are shown in Tables 11 and 12, respectively. For comparison, NGI FPF data for commercially available DPI products are summarized in Table 13. For comparison, MMAD values ​​for commercially available DPI products are summarized in Table 14. Delivered dose data for the 2 mg and 4 mg formulations of Compound I are shown in Figures 2 and 3, respectively.

[0353] [Table 12]

[0354] [Table 13]

[0355] [Table 14]

[0356] The results in Table 11 (2.0 mg Compound I) and Table 12 (4.0 mg Compound I) demonstrate that Compound I formulations exhibit favorable drug delivery efficiencies, as evidenced by FPFs of approximately 73-78%. Tables 11 and 12 also demonstrate that low MMAD values ​​(1.8-2.0 μm) are achieved when Compound I formulations are aerosolized. These data also suggest that drug delivery efficiencies are highly reproducible for Compound I formulations stored at accelerated conditions for periods including up to 24 months.

[0357] [Table 15-1] [Table 15-2]

[0358] Additionally, the FPF data obtained from formulations containing Compound I (2.0 mg, Table 11 and 4.0 mg, Table 12) are significantly higher than those reported for a range of commercially available dry powder inhalation formulations (Table 13) (Demoly et al., Respir. Med. 2014, 108, 1195).

[0359] [Table 16]

[0360] Furthermore, the MMAD values ​​obtained from formulations containing Compound I (2.0 mg, Table 11 and 4 mg, Table 12) are lower than those reported for commercially available dry powder inhalation formulations (Table 14) (Derendorf et al., Eur. Respir. J. 2006, 28, 1042).

[0361] Furthermore, both the 2 mg and 4 mg formulations containing Compound I exhibit high drug delivery efficiency, as shown by the delivered dose data in Figures 2 and 3, respectively. As shown in Figure 2, the average delivered dose for the 2 mg formulation containing Compound I is approximately 1.6 mg, or 80%. As shown in Figure 3, the average delivered dose for the 4 mg formulation containing Compound I is approximately 3.47 mg, or 87%. All individual results are well within ±20% of the average delivered dose for both the 2 mg and 4 mg formulations. Furthermore, the maximum and minimum deviations from the average delivered dose are within 10% and 16%, respectively, for the 2 mg formulation, and within 9% and 12%, respectively, for the 4 mg formulation. Therefore, the formulations containing Compound I demonstrate excellent drug delivery efficiency and reproducibility, independent of storage time and conditions.

[0362] Example 4: Animal Studies of Compound I Formulations A lactose / MgSt-based formulation of Compound I was evaluated in a 13-week inhalation toxicity study using a rat model.

[0363] The results of the toxicity studies are shown below in Table 15. No treatment effects were observed on clinical signs, body weight, food intake, ophthalmology, blood chemistry, urinalysis, or gross pathology. A NOAEL was assigned to the highest dose tested (11.9 mg / kg / day).

[0364] [Table 17]

[0365] A lactose / MgSt-based formulation of Compound I was evaluated in a 13-week inhalation toxicity study in the NHP model. The corresponding results are shown in Table 16 below. No treatment-related effects were observed on clinical signs, body weight, food intake, ophthalmology, blood chemistry, urinalysis, or gross pathology. A NOAEL was assigned to the highest dose tested (7.9 mg / kg / day).

[0366] [Table 18]

[0367] The results of the margin of safety study for the lactose / MgSt-based formulation of Compound I are shown below in Table 17. These results suggest that significant systemic and pulmonary safety margins are established for the highest daily (4 mg BID) pharmacologically active dose.

[0368] [Table 19]

[0369] Example 5: Phase 1 Clinical Trial of Formulations of Compound I A summary of the recruitment status of the Phase 1 clinical trial is shown in Table 18 below. Capsules filled with Mixture 2a were used to achieve a target dose of 0.6 mg of Compound I (3 x 0.2 mg capsules). Capsules filled with Mixture 4 were used to achieve target doses of 2.0 mg, 4.0 mg, 6.0 mg, 8.0 mg, and 12.0 mg of Compound I (1 x 2.0 mg capsule, 1 x 4.0 mg capsule, 3 x 2.0 mg capsules, 2 x 4.0 mg capsules, and 3 x 4.0 mg capsules, respectively). Twice-daily dosing (BID) was achieved by repeating the previous regimen. For example, an 8.0 mg BID dosing regimen is achieved by administering 2 x 4.0 mg capsules twice.

[0370] [Table 20]

[0371] Specific FeNO reduction data from Figure 5 are highlighted in Table 19 below. For comparison, a FeNO reduction of greater than 20% is defined as clinically significant (Am. J. Respir. Crit. Care Med. 2011, 184, 602). These results suggest that formulations containing Compound I at doses of 2.0 mg QD or greater delivered in a single capsule provide clinically meaningful FeNO reductions.

[0372] [Table 21]

[0373] Subjects in Figure 7 with FeNO levels <25 ppb on the last day of dosing (Day 10) are highlighted in Table 20 below. These results further suggest that formulations containing Compound I at doses of 2.0 mg QD or greater delivered in a single capsule result in clinically meaningful reductions in FeNO.

[0374] [Table 22]

[0375] A summary of adverse events from the Phase 1 clinical trial of Compound I (Figure 4) is shown in Table 21. No serious or serious adverse events were observed, but only mild / moderate severity adverse events were observed and were typically "unlikely related." No clinically meaningful changes were observed, as judged by the investigator, in hematology, biochemistry, or urinalysis parameters, including those affected by JAK inhibition (e.g., WBC, platelets, reticulocytes, APTT, lipids, absolute neutrophil count). No clinically meaningful changes related to treatment were observed in cardiovascular endpoints (i.e., ECG and vital signs).

[0376] [Table 23]

[0377] The FeNO reduction rate data compared to the safety margin are shown below in Table 22. The data suggest that the 4.0 mg BID dose is most likely to achieve clinical efficacy in Phase 2 clinical trials.

[0378] [Table 24]

[0379] A comparison of FeNO reduction data obtained under similar conditions using formulations of Compound I versus formulations containing the JAK1 inhibitors GDC-0214 and GDC-4379 is shown in Table 23 below. A similar comparison between formulations containing Compound I and formulations containing TD-8236 (a pan-JAK inhibitor) is shown in Figure 8, with corresponding data highlighted in Table 24. Note that patients receiving formulations containing Compound I, GDC-0214, and GDC-4379 were characterized by mild asthma and were not receiving ICS therapy. Patients receiving TD-8236 were characterized by moderate to severe asthma.

[0380] The data suggest that clinically meaningful FeNO reductions can be achieved with lower API doses and fewer capsules using the Compound I formulation compared to the GDC-0214 and GDC-4379 formulations. The data also demonstrate that in patients with moderate to severe asthma, the Compound I formulation demonstrates significantly greater FeNO reductions at a dose administered in a single capsule compared to the TD-8236 formulation.

[0381] [Table 25]

[0382] [Table 26]

[0383] Specific FeNO reduction data from Figure 9 are highlighted in Table 25 below. These results suggest that clinically meaningful FeNO reductions are achieved in patients with moderate to severe asthma using ICS / LABA background therapy after administration of a 4 mg BID regimen of a formulation containing Compound I. Each dose was delivered via a single capsule over a 10-day period. More specifically, subjects with pre-dose FeNO levels of 33-280 ppb on Day 1 demonstrated a greater than 20% reduction by Day 10, and subjects with pre-dose FeNO levels ranging from 33-118 ppb on Day 1 recorded levels below 25 ppb by Day 10.

[0384] [Table 27]

[0385] The specific FeNO reduction data from Figure 10 is highlighted below in Table 26, where greater reductions in FeNO were obtained in subjects with elevated baseline blood eosinophil levels.

[0386] [Table 28]

[0387] The specific FeNO reduction data from Figure 11 are highlighted below in Table 27. These results further suggest that formulations containing Compound I at a dose of 4.0 mg BID provide clinically meaningful FeNO reductions in patients with moderate to severe asthma using ICS / LABA background therapy.

[0388] [Table 29]

[0389] Pharmacokinetic parameters at Day 10 for Parts 2 and 3 of Phase I are summarized in Table 28 below. In Part 2, subjects with mild asthma not receiving ICS therapy received four different dose regimens over 10 days. Each separate cohort consisted of six subjects receiving active treatment and two subjects receiving a matching placebo. Blood samples were collected to measure Compound I plasma concentrations. The resulting data were used to determine PK parameters at Day 10, representing the day the final dose was administered. Dose regimens ranging from 2 mg QD to 8 mg BID were considered pharmacologically active, as evidenced by clinically meaningful placebo-corrected mean FeNO changes from pre-dose on Day 1 to Day 10. 0.6 mg QD was identified as the lowest active dose at which the placebo-corrected mean FeNO change was below the 20% threshold used to determine clinical relevance.

[0390] In Part 3, subjects with moderate to severe asthma treated with ISC / LABA background therapy (17 active, 6 placebo) received a single-dose regimen (4 mg BID) for 10 days. Blood samples were collected to measure plasma KN-002 concentrations. Pharmacokinetic parameters were determined on Day 10, representing the day the final dose was administered.

[0391] [Table 30-1] [Table 30-2]

[0392] Sputum and serum inflammatory biomarkers on day 10 are shown in Table 29 below. In Part 3, sputum samples collected by sputum induction were evaluated according to the European Respiratory Society guidelines (Paggiaro, et al., Eur. Respir. J. 2002, 20:Suppl. 37, 3s). Subjects were randomly assigned to a sputum-producing group and a non-sputum-producing group, with a minimum goal of approximately 50% of subjects being able to provide adequate sputum samples at screening. Subjects in the sputum-producing group underwent a second sputum induction after 10 days of treatment with 4 mg Compound I BID or placebo. Differential cell counts (DCC) were performed on samples deemed appropriate according to standard procedures, and patients with evaluable baseline (screening) and post-treatment samples at day 10 (or day 11 if day 10 was not appropriate) were included in analyses including individual and mean absolute eosinophil counts and differential eosinophil percentages.

[0393] In the sputum-producing group, six Compound I (active) subjects and two placebo subjects were identified with adequate baseline and post-treatment sputum samples. The resulting data were used to determine the percent change from baseline, mean percent change from baseline, and placebo-adjusted mean percent change from baseline (Compound I vs. placebo). As reported below, improvements (reductions) from baseline were observed in both individual and mean absolute eosinophil counts and eosinophil differential percentages in all active-treated subjects, whereas no improvement was observed in either parameter in placebo subjects. The placebo-adjusted mean percent change from baseline demonstrated similar improvements in absolute eosinophil counts and eosinophil differential percentages. At baseline, all subjects had eosinophil differential percentages greater than 3%, indicating active eosinophilic inflammation. By day 10, 66% (4 / 6) of active treatment subjects had improved to <3% eosinophils, and 50% (3 / 6) were below the more stringent decision threshold of 1.9% (Reddel et al., Am. J. Respir. Crit. Care Med. 2009, 180, 59). Placebo subjects showed no improvement. These findings support the pharmacodynamic involvement of Compound I at its site of action (the airway) and demonstrate a clinically meaningful effect on eosinophilic inflammation after 10 days of treatment.

[0394] Whole blood hematology samples were collected from all patients on Day 1 (baseline) and Day 10 before dosing. Parameters including absolute whole blood eosinophil count and eosinophil differential percentage were determined, and the resulting data were used to determine the percent change from baseline, mean percent change from baseline, and placebo-corrected mean percent change from baseline (Compound I vs. placebo). As reported below, improvements (decreases) from baseline were observed in 83% (5 / 6) of active treatment subjects, with only minor decreases observed in both placebo treatment subjects. Decreases (improvements) in mean absolute eosinophil count and mean eosinophil differential percentage were observed in active treatment-treated subjects, and the placebo-corrected mean percent change from baseline values ​​similarly reflected improvements in this marker of eosinophilic inflammation.

[0395] [Table 31-1] [Table 31-2]

[0396] Although the formulations of the present disclosure have been described in some detail by way of examples and examples for the purpose of clear understanding, it is clear to those skilled in the art that certain changes and modifications can be made within the scope of the appended claims.In addition, all U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification are incorporated herein by reference in their entirety to the extent that they do not contradict this description.If there is any contradiction between this application and the references listed herein, this application shall prevail.

Claims

1. (a) (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, (b) magnesium stearate, and (c) A pharmaceutical formulation comprising lactose.

2. The formulation comprises: (a) 0.5 to 11.0% by weight of Compound I or a pharmaceutically acceptable salt thereof; (b) 0.5 to 2.0 wt. % magnesium stearate, and 2. The pharmaceutical formulation of claim 1, comprising: (c) 87.0 to 99.0% by weight of lactose.

3. The formulation comprises: (a) about 1.1% by weight of Compound I or a pharmaceutically acceptable salt thereof; (b) about 1.0% by weight of magnesium stearate, and 3. The pharmaceutical formulation of claim 1 or claim 2, comprising (c) about 97.9% by weight of lactose.

4. The formulation comprises: (a) about 10.3% by weight of Compound I or a pharmaceutically acceptable salt thereof; (b) about 1.2% by weight of magnesium stearate, and 3. The pharmaceutical formulation of claim 1 or claim 2, comprising (c) about 88.5% by weight of lactose.

5. The formulation comprises: (a) 1.0 to 5.0 mg of Compound I or a pharmaceutically acceptable salt thereof; (b) 0.1 to 1.0 mg magnesium stearate, and 2. The pharmaceutical formulation of claim 1, comprising: (c) 15.0 to 37.0 mg of lactose.

6. The formulation comprises: (a) 0.1 to 1.0 mg of Compound I or a pharmaceutically acceptable salt thereof; (b) 0.1 to 1.0 mg magnesium stearate, and 2. The pharmaceutical formulation of claim 1, comprising: (c) 18.0 to 20.0 mg of lactose.

7. The formulation comprises: (a) about 0.2 mg of Compound I or a pharmaceutically acceptable salt thereof; (b) about 0.2 mg magnesium stearate, and 10. The pharmaceutical formulation of claim 1 or claim 6, comprising (c) about 19.6 mg of lactose.

8. The formulation comprises: (a) about 2.1 mg of Compound I or a pharmaceutically acceptable salt thereof; (b) about 0.3 mg magnesium stearate, and 10. The pharmaceutical formulation of claim 1 or claim 5, comprising (c) about 17.7 mg of lactose.

9. The formulation comprises: (a) about 4.1 mg of Compound I or a pharmaceutically acceptable salt thereof; (b) about 0.5 mg magnesium stearate, and 10. The pharmaceutical formulation of claim 1 or claim 5, comprising (c) about 35.4 mg of lactose.

10. 10. The pharmaceutical formulation of any one of claims 1 to 9, wherein the content uniformity of the pharmaceutical formulation of Compound I has a relative standard deviation percent (RSD) of about 5% or less.

11. The pharmaceutical formulation of any one of claims 1 to 10, wherein the formulation is suitable for aerosolized delivery to a subject.

12. 12. The pharmaceutical formulation of claim 11, having a mass median aerodynamic diameter (MMAD) of about 5.0 μm or less when aerosolized.

13. 13. The pharmaceutical formulation of claim 11 or claim 12, wherein upon aerosolization, the fine particle fraction (FPF) of Compound I is greater than or equal to about 60%.

14. 14. The pharmaceutical formulation of any one of claims 11 to 13, wherein a capsule containing about 1.0 to 3.0 mg of Compound I, when aerosolized, provides a fine particle mass (FPM) of Compound I of 900 to 1800 μg.

15. 15. The pharmaceutical formulation of any one of claims 11 to 14, wherein the FPM of Compound I is 1750 to 2350 μg when a capsule containing about 3.0 to 5.0 mg of Compound I is aerosolized.

16. 16. The pharmaceutical formulation of any one of claims 11 to 15, wherein, upon aerosolization, the delivered dose of Compound I is at least about 80% of the target dose.

17. Compound I has the following activity against copper Kα1: Approximately 8.25°, Approximately 13.25°, Approximately 15.40°, approximately 17.65°, and 17. The pharmaceutical formulation of any one of claims 11 to 16, which is a polymorphic form (Form II) having a diffraction angle (2θ) of about 25.39°.

18. 18. A method for treating asthma, COPD, or an inflammatory disease associated with eosinophilic or non-eosinophilic inflammation in a subject in need thereof, the method comprising administering to the subject the pharmaceutical formulation of any one of claims 1 to 17.

19. A method for treating asthma, COPD, or an inflammatory disease associated with eosinophilic inflammation or non-eosinophilic inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof.

20. 20. The method of claim 18 or 19, wherein the inflammatory disease associated with eosinophilic inflammation or non-eosinophilic inflammation is eosinophilic asthma, nasal polyps, rhinitis, fibrotic lung disease, interstitial lung disease, or pulmonary hypertension.

21. A method for reducing exhaled nitric oxide (FeNO) levels in a subject, the method comprising administering to a subject in need of reduced FeNO levels a pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof.

22. 20. A method for reducing FeNO levels in a subject, comprising administering to a subject in need thereof a pharmaceutical formulation according to any one of claims 1 to 17.

23. 23. The method of any one of claims 18 to 22, wherein the FeNO concentration in the subject is reduced to at least about 35 ppb (ppb is parts per billion).

24. 24. The method of claim 23, wherein the FeNO concentration in the subject is reduced to at least about 30 ppb.

25. 25. The method of claim 23 or claim 24, wherein the FeNO concentration in the subject is reduced to at least about 25 ppb.

26. 26. The method of any one of claims 23 to 25, wherein the FeNO concentration in the subject is reduced to at least about 20 ppb.

27. 27. The method of any one of claims 23 to 26, wherein the FeNO concentration in the subject is reduced below the FeNO concentration in the subject prior to administration.

28. 23. The method of any one of claims 18 to 22, wherein the FeNO concentration in the subject is reduced by at least about 20%.

29. 29. The method of claim 28, wherein the FeNO concentration in the subject is reduced by at least about 30%.

30. 30. The method of claim 28 or claim 29, wherein the FeNO concentration in the subject is reduced by at least about 40%.

31. 31. The method of any one of claims 28-30, wherein the FeNO concentration in the subject is reduced by at least about 50%.

32. 32. The method of any one of claims 28-31, wherein the FeNO concentration in the subject is reduced by at least about 60%.

33. 33. The method of any one of claims 28-32, wherein the FeNO concentration in the subject is reduced by at least about 65%.

34. 34. The method of any one of claims 28 to 33, wherein the FeNO concentration in the subject is reduced by at least about 80%.

35. 35. The method of any one of claims 28 to 34, wherein the subject's FeNO concentration is reduced below the subject's FeNO concentration before administration and below the FeNO concentration during placebo treatment.

36. 36. The method of any one of claims 18 to 35, wherein the formulation further comprises lactose and magnesium stearate.

37. The method of any one of claims 18 to 36, wherein the formulation is administered as a single capsule.

38. 38. The method of any one of claims 18 to 37, wherein the subject has moderate to severe asthma.

39. 39. The method of claim 38, wherein the subject's moderate to severe asthma is characterized by high Th2 expression.

40. 1. A process for preparing a dry powder pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I), comprising: (a) preparing a first premix by mixing (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound I) or a pharmaceutically acceptable salt thereof with magnesium stearate; (b) mixing magnesium stearate and lactose to form a second preblend; (c) mixing the first pre-mix with the second pre-mix; (d) co-grinding the product prepared in step (c); (e) mixing the products prepared in step (d) to prepare the formulation.

41. 41. The method of claim 40, wherein a portion of the second pre-mixture is co-milled prior to step (c).

42. 42. The method of claim 40 or claim 41, wherein the first pre-blend has 4.0 to 14.0 wt. % magnesium stearate.

43. 43. The method of any one of claims 40 to 42, wherein the second pre-blend has 0.4 to 1.1 wt% magnesium stearate.

44. 1. A process for preparing a dry powder pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile, comprising: (a) mixing (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof with magnesium stearate to prepare a first premix; (b) mixing magnesium stearate and lactose to form a second preblend; (c) mixing the first pre-mix and the second pre-mix together to prepare the formulation; (d) allowing the formulation to stand for 10 to 120 hours.

45. 45. The method of claim 44, wherein the standing step (d) is for 15 to 65 hours.

46. 46. ​​The method of claim 44 or claim 45, wherein the first pre-mixture and the second pre-mixture are each separately co-milled prior to step (c).

47. The method according to any one of claims 44 to 46, wherein the premixture of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate contains 4.0 to 14.0% by weight of magnesium stearate.

48. The method according to any one of claims 44 to 47, wherein the premixture of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate contains 4.0 to 8.0% by weight of magnesium stearate.

49. 49. The method of any one of claims 44 to 48, wherein the pre-mixture of lactose and magnesium stearate has 0.4 to 1.1% by weight of magnesium stearate.

50. 50. The method of any one of claims 44 to 49, wherein the pre-mixture of lactose and magnesium stearate has 0.8 to 1.1% by weight of magnesium stearate.

51. 51. The method of any one of claims 44 to 50, wherein step (c) is carried out by TRV mixing.

52. 52. The method of any one of claims 44 to 51, comprising the additional step of: (e) filling a capsule with the formulation.

53. 1. A process for preparing a dry powder pharmaceutical formulation comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile, comprising: (a) co-milling (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof with magnesium stearate to prepare a first preblend; (b) co-milling magnesium stearate and lactose to prepare a second pre-blend; (c) mixing the first pre-mix and the second pre-mix together to prepare the formulation.

54. 54. The method of claim 53, wherein the premix of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate contains 4.0 to 14.0% by weight of magnesium stearate.

55. The method according to claim 53 or 54, wherein the premixture of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3-oxopropanenitrile and magnesium stearate contains 4.0 to 8.0% by weight of magnesium stearate.

56. 56. The method of any one of claims 53 to 55, wherein the pre-mixture of lactose and magnesium stearate has 0.4 to 1.1% by weight of magnesium stearate.

57. 57. The method of any one of claims 53 to 56, wherein the pre-mixture of lactose and magnesium stearate has 0.8 to 1.1% by weight of magnesium stearate.

58. 58. The method of any one of claims 53 to 57, comprising the additional step of: (d) allowing the formulation to stand for 10 to 120 hours.

59. 59. The method of any one of claims 53 to 58, comprising the additional step of: (d) allowing the formulation to stand for 15 to 65 hours.

60. 60. The method of any one of claims 53 to 59, wherein step (c) is carried out by TRV mixing.

61. 61. The method of any one of claims 53 to 60, comprising the additional step of: (e) filling a capsule with the formulation.

62. A method according to any one of claims 40 to 61, wherein the method is carried out without the use of plastic powder handling materials.

63. 63. The method of any one of claims 40 to 62, wherein the plastic powder handling material is a plastic spatula, a plastic scoop, or a plastic transfer bag.

64. 64. The method of claim 63, wherein the plastic transfer bag is a ChargeBag®.

65. A method according to any one of claims 40 to 64, wherein the method is carried out using powder handling material made from stainless steel.

66. 66. The method of claim 65, wherein the stainless steel powder handling material is a stainless steel spatula, a stainless steel scoop, a stainless steel funnel, or a stainless steel container.

67. A dry powder pharmaceutical formulation prepared by the method of any one of claims 40 to 66.

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