WO2025195451A1

WO2025195451A1 - Pharmaceutical compositions, dosage forms, and methods of preparation and use thereof

Info

Publication number: WO2025195451A1
Application number: PCT/CN2025/083707
Authority: WO
Inventors: Yuanyuan Zhang; Weiyi Li; Xiaodong Li; Michael Lawrence Vazquez; Zhaokui WAN; David Waller; Dileep Kumar BOINIPALLY; Amy MCCUSKER; Erica WINTER; Stacia WEGST-UHRICH; Brian SLAFER; Matthew GARROW; Clemence CHEVENAS-PAULE; Lee Thompson
Original assignee: Lynk Pharmaceuticals Co Ltd
Current assignee: Lynk Pharmaceuticals Co Ltd
Priority date: 2024-03-21
Filing date: 2025-03-20
Publication date: 2025-09-25
Anticipated expiration: 2026-09-21

Abstract

Disclosed are a pharmaceutical composition comprising a compound of formula (I) as an active ingredient for inhibiting JAK, or treating JAK-mediated disease or disorder, a process for preparing the same and use of the same. The pharmaceutical composition has an advantage of high dissolution, and further has one or more advantages such as extended release, good pharmacokinetic properties.

Description

PHARMACEUTICAL COMPOSITIONS, DOSAGE FORMS, AND METHODS OF PREPARATION AND USE THEREOF

Priority Claims and Related Patent Applications

This application claims the benefit of priority to PCT International application No. PCT/CN2024/082984, filed March 21, 2024, the entire content of which is incorporated herein by reference for all purposes.
Technical Fields of the Invention

The present disclosure generally relates to therapeutic compositions and methods of use thereof. More particularly, the invention provides novel pharmaceutical compositions and dosage forms, and preparation methods and therapeutic use thereof.

Background of the Invention

Development of pharmaceutical compositions comprising one or more novel active ingredients requires a variety of considerations, such as route of administration, dosage form, strength of active ingredient (s) , non-therapeutic component (s) (e.g., excipients) and their respective amounts. Each of these considerations may involve additional considerations such as stability, degradation, sensitivity to light, solubility, target pharmacokinetic profile, taste if administered enterally, palatability, pH, skin irritability, microbial growth, etc. Advancing a novel active ingredient, e.g., a JAK1 inhibitor, requires development of pharmaceutical compositions and dosage forms that address these, or other, considerations.

Moreover, drug product properties are affected by various formulation variables. For example, a wide particle size distribution of the drug substance may adversely impact blend flowability; filler concentration, particle size and density can impact the flow properties of the blend; filler type and level can impact tablet compressibility and total insoluble content of the formulation thereby influencing diffusion/erosion and dissolution rate; hydration and concentration of polymer influence the rate of diffusion; polymer concentration can impact the flow properties of the blend, demonstrating blend segregation and/or poor powder flow during tablet compression to cause significant weight variation; certain acidulants may result in varying levels of mottled appearance when exposed to ambient and accelerated conditions unprotected without appropriate packaging; and concentration, particle size and density of acidulants can impact the flow properties of the blend.

Accordingly, there is a need for pharmaceutical compositions and dosage forms comprising therapeutic agents, e.g., JAK1 inhibitors, that exhibit desirable properties such as good stability, degradation, solubility, and pharmacokinetic profiles and are suitable for safe and effective use by patients.

Summary of the Invention

The invention is based in part on novel pharmaceutical compositions and dosage forms of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, having suitable properties (e.g., stability, degradation, solubility, and pharmacokinetic profiles) . The invention also provides methods for preparation thereof and therapeutic use in treatment of various diseases and conditions.

Pharmaceutical compositions and dosage forms of the invention overcome the disadvantage of low dissolution of the compound of formula (I) , and further overcome one or more additional disadvantages of existing formulations, such as immediate release, poor pharmacokinetic properties, etc. The pharmaceutical composition of the present disclosure has an advantage of high dissolution, and further has one or more advantages such as extended release, good pharmacokinetic properties, etc.

In one aspect, the invention generally relates to a pharmaceutical composition that comprises:
(a) a compound of formula (I)

or a pharmaceutically acceptable salt thereof;
(b) a filler; and
(c) a first polymeric release-controlling excipient;
wherein the first polymeric release-controlling agent has a viscosity of about 80 to about 120 mPa·s.

In certain embodiments, the pharmaceutical composition further comprises:
(d) a second polymeric release-controlling excipient;
(e) an acidulant;
(f) a glidant; and/or
(g) a lubricant.

In another aspect, the invention generally relates to a unit dosage form comprising the pharmaceutical composition, wherein the unit dosage form is preferable in the form of a tablet; optionally, the tablet is coated with one or more compendial excipients.

In yet another aspect, the invention generally relates to a method for treating a JAK1-mediated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition or the unit dosage form disclosed herein.

In yet another aspect, the invention generally relates to se of the pharmaceutical composition of the invention in the manufacture of a medicament for treating a JAK1-mediated disease or disorder.

In yet another aspect, the invention generally relates to a process for preparing the pharmaceutical composition as described herein, comprising: (a) blending the compound of formula (I) and the filler to obtain a first blend; (b) blending the first blend with the first polymeric release-controlling agent, optionally the second polymeric release-controlling agent, optionally the acidulant, and optionally the glidant to obtain a second blend; and (c) blending the second blend with the lubricant to obtain the pharmaceutical composition.

Brief Description of the Drawings

FIG. 1 is an exemplary XRPD pattern of the crystalline form B of the compound of formula (I) .

FIG. 2 illustrates an exemplary manufacturing process for preparing extended-release tablet formulations of a compound of Formula (I) .

FIG. 3 shows exemplary dissolution profiles for formulations varying in polymeric release-controlling agents.

FIG. 4 shows exemplary dissolution profiles for formulations comprising fumaric acid.

FIG. 5 shows exemplary dissolution profiles for formulations with and without fumaric acid at 30%w/w HPMC K100 LV.

FIG. 6 shows exemplary dissolution profiles for formulations comprising tartaric acid.

FIG. 7 shows exemplary dissolution profiles for formulations with and without tartaric acid at 30%HPMC K100 LV.

FIG. 8 shows exemplary dissolution profiles for formulations comprising tartaric acid or fumaric acid at 30%HPMC K100 LV.

FIG. 9 shows exemplary dissolution profiles for formulations comprising fumaric and tartaric acids.

FIG. 10 shows exemplary dissolution profiles for formulations comprising tartaric acid and varying levels of fumaric acid.

FIG. 11 shows exemplary dissolution profiles for formulations comprising acidulants and varying amounts of polymeric release-controlling agents.

FIG. 12 shows exemplary dissolution profiles for formulations comprising varying levels of filler.

FIG. 13 shows exemplary dissolution profiles for formulations varying in tablet weight or size.

FIG. 14 shows exemplary dissolution profiles for formulations varying in API weight.

FIG. 15 shows exemplary dissolution profiles for formulations administered to humans.

FIG. 16 shows exemplary dissolution profiles for formulations administered to humans.

FIG. 17 shows a semi-log plot of the C-T profiles for cohorts 1-6 (C1-C6) for the extended-release formulations in comparison with the immediate release formulation.

FIG. 18 shows exemplary dissolution profiles for exemplary formulations.

FIG. 19 shows exemplary dissolution profiles in two stage and release test method for Batch B6.

FIG. 20 shows exemplary dissolution profile of the 20 mg formulation in comparison with Formulation 55 comprising 40 mg of the compound of formula (I) .

FIG. 21 shows the comparison of mean C-T profiles of the 20 mg tablet (cohort 8) , 40 mg tablet (cohort 6, Formulation 55) , and 80 mg dose/tablet (cohort 7) .

FIG. 22 shows the comparison of the PK profiles of Upadacitinib ER (15mg) and ER19 (adjusted to 15mg) .
Definitions

Unless expressly indicated otherwise or the context in which they are used indicates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present disclosure and/or in methods of the present disclosure, unless otherwise understood from the context. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element (s) can be removed from the group. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention (s) . For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention (s) described and depicted herein.

The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, in certain contexts, “an element” means one element and/or in certain contexts more than one element. By way of another example, in certain contexts “afiller” means one filler and/or in certain contexts more than one filler (e.g., a mixture of two or more fillers) .

The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

It should be understood that the expression “at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

The use of the term “include” , “includes” , “including” , “have” , “has” , “having” , “contain” , “contains” , “containing” , “comprises” , or “comprising” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

Where the use of the term “about” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10%variation from the nominal value unless otherwise indicated or inferred from the context.

At various places in the present specification, variables or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual sub-combination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

The use of any and all examples, or exemplary language herein, for example, “such as” or “including” is intended merely to illustrate better the present disclosure and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

As used herein, the term “dissolution profile” refers to dissolution testing of a drug substance or drug product at multiple time points. Dissolution profiles for drug substances (e.g., the compound of formula (I) ) or drug products (e.g., the pharmaceutical compositions described herein) may be performed for characterization and quality control to ensure the drug is released at a defined range of rates in a well-defined dissolution aqueous media that is at least sink conditions for that drug, or in biorelevant media such as simulated gastric or intestinal fluids representing either the fasted or fed states. In certain cases, but not others, dissolution testing may be predictive of or give insight into in vivo bioavailability of the drug substance. Dissolution testing may be performed using USP testing protocols and dissolution apparatus.

As used herein, a “release-controlling excipient” is an excipient material with the primary function for modifying the duration of release of an active drug substance, e.g., a JAK1 inhibitor of formula (I) , or a pharmaceutically acceptable salt thereon, from a dosage form by, for example, swelling and/or forming a viscous substance or gel in water and/or at a certain pH. In certain embodiments, the release-control excipient is a polymeric material. A polymeric release-controlling excipient may function to extend the release rate of the active ingredients by forming a viscous gel in fluid. In certain embodiments, the release-controlling excipient is selected from the group consisting of hydroxypropylmethyl cellulose (HPMC) , a copolymer of acrylic acid crosslinked with a polyalkenyl polyether, and combinations thereof. In certain embodiments, polymeric release-controlling excipients include, but are not limited to, HPMC (e.g. K100 E50, E25, K4M) , hydroxyethyl cellulose (HEC) , hypromellose phthalate (HPMCP) , hydroxypropyl methylcellulose acetate succinate (HPMCAS) , polyvinyl acetate phthalate (PVAP) , and Carbopol.

As used herein, the term “filler” is a substance that is added to increase its size or weight. Fillers include but are not limited to MCC, lactose, mannitol.

As used herein, the term “acidulant” is a material used to add acidity to drug products which can modify the release rate of active ingredient. Acidulants include but are not limited to citric acid, malic acid, succinic acid, tartaric acid, maleic acid, fumaric acid.

As used herein, the term “functional film coating" has an influence on the drug release and is used to modify the release of the active pharmaceutical ingredient (API) and achieve the desired tablet performance, e.g., to achieve an odor or taste masking of APIs that are bitter or bad of smell. Furthermore, it is possible to protect the API against environmental influences such as oxidation, UV radiation and moisture. Other functions include the targeted or delayed release of the active ingredient, protection against stomach acid or protection of mucous membrane and reduction of side effects. The term non-functional film coating is not related to the API. It is more for aesthetic, mechanical stability, marketing reasons (color) or easier intake (swallowability) .

As used herein, the term “granulation” refers to a process of forming granules from a powdered or particulate material. As used herein, “Dry granulation” refers to a process in which granules are formed without the presence of a liquid solution and may be useful in the preparation of granules of materials sensitive to heat, moisture, or solvents. For example, roller compaction is a dry granulation process. As used herein, “Wet granulation” refers to the formation of granules wherein the particles are bound together using a binder or a liquid solution. Examples of wet granulation are high shear granulation and fluid bed granulation.

As used herein, the term “sieving” refers to putting or passing a particulate solid (e.g., a compound of formula (I) ) through a utensil having a plurality of meshed or perforated openings, slits, or holes, e.g., to separate fine particles of loss matter from coarser ones.

The term “blending” refers to the mixing of pharmaceutical ingredients to form a mixture of the ingredients, e.g. active pharmaceutical ingredient (API) and pharmaceutically acceptable carrier (s) , as defined by pharmaceutical specifications in the compendial references using a variety of equipment such as, but not limited to, “V” -blenders, bin-blenders, cone-blenders.

As used herein, the term “pharmaceutical composition” or “pharmaceutical formulation” refer to the composition of a therapeutically active agent with one or more pharmaceutically acceptable excipients, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

As used herein, the term “pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and/or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or human, as appropriate; or means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

As used herein, the term “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure (e.g., the compound of formula (I) ) , which salt is compatible with pharmaceutical administration.

As is known to those of skill in the art, “salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their
pharmaceutically acceptable acid addition salts.

Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1-4 alkyl, and the like.

Examples of salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na⁺, K⁺, Ca²⁺, NH⁴⁺, and NW⁴⁺ (where W can be a C_1-4 alkyl group) , and the like.

For therapeutic use, salts of the compounds of the present disclosure are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

As used herein, the term “extended release” refers to part or all of a composition or dosage form that release one or more active pharmaceutical ingredients over a prolonged period of time (e.g., over a period of at least more than 1 hour) , or delays the release of active pharmaceutical ingredients for a prolonged period of time. The characteristic of extended release (ER) may also be referred to as sustained release (SR) , prolonged release (PR) , modified release (MR) , delayed release (DR) or controlled release (CR) . When used in association with the dissolution profiles discussed herein, the term “extended release” refers to that portion of a composition dosage form according to the present disclosure that delivers active pharmaceutical ingredient over a period of time greater than 1 hour.
As used herein, “immediate release” refers to part or all of a composition or dosage form that releases
active pharmaceutical ingredients substantially immediately upon contact with gastric juices and that results in substantially complete dissolution within, e.g., about 1 hour. The characteristic of immediate release (IR) may also be referred to as instant release (IR) .

As used herein, the term “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include binders, diluents, carriers, adjuvants, fillers (e.g., brittle diluents or fillers and ductile diluents or fillers) , disintegrants, lubricants, coatings, sweeteners, flavors, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxypropylmethylcellulose, polyvinyl pyrrolidine, and colors, and the like. For examples of excipients, see Gennaro, Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publ. Co., Easton, PA (1990) or Shesky, Hancock, Moss and Goldfarb, Handbook of Pharmaceutical Excipients, 9th Ed. Pharmaceutical Press, London, UK (2020) .

Examples of diluents or fillers include, but are not limited to, a sugar (e.g., mannitol, lactose, lactose monohydrate, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, polydextrose, and combinations thereof) , an inorganic material (e.g., dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, bentonite, kaolin) , calcium lactate, a starch (e.g., a pregelatinized starch) , a microcrystalline cellulose, a silicified microcrystalline cellulose, a polysaccharide, a cellulose (e.g., a hydroxypropylcellulose, a hypromellose, a carboxymethylcellulose, a methylcellulose, a hydroxypropylmethylcellulose, a hydroxyethylcellulose) , a dextrin, a maltodextrin, an alginate, a collagen, a polyvinylpyrrolidone, a polyvinylacrylate, polyethylene oxide, and polyethylene glycol. Sugar is defined herein to include sugar alcohols.
Examples of disintegrants include, but are not limited to, alginic acid, an alginate, primogel, a
cellulose (e.g., hydroxypropylcellulose) , polacrillin potassium, sodium starch glycolate, sodium croscarmellose, a polyplasdone (e.g., a crospovidone) , and a starch (e.g., corn starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch) .

Examples of binders include, but are not limited to, a hydroxypropylcellulose, hydroxyethylcellulose, a hydroxypropylmethycellulose (e.g., a low viscosity hydroxypropylmethycellulose) , a sugar, a polyvinylpyrrolidone, a polyvinyl alcohol, a polyvinyl acetate, a polydextrose, a chitosan, a carrageenan, carbophil, a microcrystalline cellulose, gum tragacanth, guar gum, gellan gum, gelatin, and a starch (e.g., corn starch) .

Examples of wetting agents include, but are not limited to, a poloxamer (e.g., poloxamer 407) , sodium dodecyl sulfate, sodium lauryl sulfate (SLS) , sodium stearyl fumarate (SSF) , a polydimethylsiloxane, a polysorbate (e.g., polyoxyethylene 20 sorbitan mono-oleate (20) ) , sorbitan monooleate, sorbitan trioleate, sorbitan laurate, sorbitan stearate, sorbitan monopalmitate, lecithin, sodium taurocholate, ursodeoxycholate, polyethoxylated castor oil, cetyl trimethylammonium bromide, nonoxynol, á-tocopherol polyethylene glycol 1000 succinate, and docusate sodium.

Examples of lubricants and glidants include, but are not limited to, a wax, a glyceride, a light mineral oil, a polyethylene glycol, sodium stearyl fumarate, magnesium stearate, stearic acid, hydrogenated oil (e.g., hydrogenated vegetable oil) , an alkyl sulfate, sodium benzoate, sodium acetate, glyceryl behenate, palmitic acid, and coconut oil.

Examples of glidants include, but are not limited to, colloidal silicon dioxide, colloidal silicon dioxide, talc, kaolin, bentonite, and activated carbon/charcoal.

Examples of colorants include, but are not limited to, titanium dioxide, aluminum lakes, iron oxides and carbon black.

Examples of coatings include but are not limited to, a film forming polymer (e.g., a hypromellose, a methyl cellulose, an ethylcellulose, cellulose acetate, a hydroxypropylmethyl cellulose, a hydroxypropyl cellulose, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, a polyvinylpyrrolidone, polyvinyl alcohol, a Eudragit/acrylate) and a plasticizer (e.g., triacetin, polyethylene glycol, propylene glycol) .

Pharmaceutical compositions for oral administration (e.g., pharmaceutical compositions of the compound of formula (I) described herein) can take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pills, tablets, capsules or the like in the case of solid compositions.

A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult) ) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys) , cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

As used herein, the term “solid dosage form” means a pharmaceutical dose (s) in solid form, e.g., tablets, capsules, granules, powders, minitabs, sachets, stickpacks, reconstitutable powders, dry powder inhalers, lozenges, and chewables.

As used herein, the terms “administering” or “administration” refer to oral administration, administration as a pulmonary, suppository, intramuscular administration, intrathecal administration, intranasal administration or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or) . Parenteral administration includes, e.g., intramuscular and subcutaneous. Other modes of delivery include, but are not limited to, the use of liposomal formulations, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., therapeutic agent, chemotherapeutic, or treatment for a neurodegenerative disease) . The compound of formula (I) can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent) . Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation) .

The terms “disease, ” “disorder, ” and “condition” are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat, ” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ( “therapeutic treatment” ) , and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ( “prophylactic treatment” ) . In one embodiment, the compounds provided herein are contemplated to be used in methods of therapeutic treatment wherein the action occurs while a subject is suffering from the specified disease, disorder or condition and results in a reduction in the severity of the disease, disorder or condition, or retardation or slowing of the progression of the disease, disorder or condition. In an alternate embodiment, the compounds provided herein are contemplated to be used in methods of prophylactic treatment wherein the action occurs before a subject begins to suffer from the specified disease, disorder or condition and results in preventing a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or preventing the recurrence of the disease, disorder or condition.

In general, an “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response e.g., to treat a disease or disorder described herein. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment (i.e., encompasses a “therapeutically effective amount” and a “prophylactically effective amount” ) .

As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the therapeutic treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the therapeutic treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

Detailed Description of the Invention

The invention provides novel pharmaceutical compositions and dosage forms (e.g., solid oral dosage forms) of a compound of formula (I) , or a or a pharmaceutically acceptable salt thereof. The invention additionally provides methods for preparation thereof and therapeutic use in treatment of various diseases and conditions.

The pharmaceutical compositions and dosage forms of the invention exhibit high dissolution, extended release, good stability, suitable solubility, and/or other suitable overall pharmacokinetic profiles.

In some embodiments, the compound of formula (I) is a crystalline form B of the compound of formula (I) , wherein the crystalline form B has an X-ray powder diffraction (XRPD) pattern comprising characteristic diffraction peaks at the following 2θ angles: 10.815°±0.2°, 13.475°±0.2°, 17.225°±0.2°, 21.804°±0.2°, and 22.361°±0.2°, with a radiation source of Cu-Kα.

In some embodiments of the present disclosure, the XRPD pattern of the crystalline form B further has one or more than one of characteristic diffraction peaks at the following 2θangles: 9.959°±0.2°, 11.757°±0.2°, 14.974°±0.2°, 20.481°±0.2°, 21.033°±0.2°, 21.544°±0.2°, 23.462°±0.2°, 23.687°±0.2°, 25.155°±0.2°, 29.747°±0.2°, 30.292°±0.2°, and 38.075°±0.2°, with a radiation source of Cu-Kα.

In some embodiments of the present disclosure, the XRPD pattern of the crystalline form B has characteristic diffraction peaks at the following 2θ angles: 9.959°±0.2°, 10.815°±0.2°, 11.757°±0.2°, 13.475°±0.2°, 14.974°±0.2°, 17.225°±0.2°, 20.481°±0.2°, 21.033°±0.2°, 21.544°±0.2°, 21.804°±0.2°, 22.361°±0.2°, 23.462°±0.2°, 23.687°±0.2°, 25.155°±0.2°, 29.747°±0.2°, 30.292°±0.2°, and 38.075°±0.2°, with a radiation source of Cu-Kα.

In some embodiments of the present disclosure, the XRPD pattern of the crystalline form B further has one or more than one of characteristic diffraction peaks at the following 2θangles: 10.092°±0.2°, 13.198°±0.2°, 16.360°±0.2°, 16.784°±0.2°, 17.918°±0.2°, 18.347°±0.2°, 19.243°±0.2°, 20.062°±0.2°, 22.774°±0.2°, 24.153°±0.2°, 24.906°±0.2°, 26.188°±0.2°, 26.697°±0.2°, 27.787°±0.2°, 28.192°±0.2°, 30.957°±0.2°, 31.486°±0.2°, 32.819°±0.2°, 32.973°±0.2°, 33.579°±0.2°, 34.573°±0.2°, 34.939°±0.2°, 35.947°±0.2°, 36.722°±0.2°, 36.954°±0.2°, 39.153°±0.2°, and 39.714°±0.2°, with a radiation source of Cu-Kα.

In some embodiments of the present disclosure, the XRPD pattern of the crystalline form B has characteristic diffraction peaks at the following 2θ angles: 9.959°±0.2°, 10.092°±0.2°, 10.815°±0.2°, 11.757°±0.2°, 13.198°±0.2°, 13.475°±0.2°, 14.974°±0.2°, 16.360°±0.2°, 16.784°±0.2°, 17.225°±0.2°, 17.918°±0.2°, 18.347°±0.2°, 19.243°±0.2°, 20.062°±0.2°, 20.481°±0.2°, 21.033°±0.2°, 21.544°±0.2°, 21.804°±0.2°, 22.361°±0.2°, 22.774°±0.2°, 23.462°±0.2°, 23.687°±0.2°, 24.153°±0.2°, 24.906°±0.2°, 25.155°±0.2°, 26.188°±0.2°, 26.697°±0.2°, 27.787°±0.2°, 28.192°±0.2°, 29.747°±0.2°, 30.292°±0.2°, 30.957°±0.2°, 31.486°±0.2°, 32.819°±0.2°, 32.973°±0.2°, 33.579°±0.2°, 34.573°±0.2°, 34.939°±0.2°, 35.947°±0.2°, 36.722°±0.2°, 36.954°±0.2°, 38.075°±0.2°, 39.153°±0.2°, and 39.714°±0.2°, with a radiation source of Cu-Kα.

In some embodiments, the pharmaceutical composition further comprises:
(d) a second polymeric release-controlling agent.

In some embodiments, the pharmaceutical composition further comprises:
(e) an acidulant.

In some embodiments, the pharmaceutical composition further comprises:
(f) a glidant.

In some embodiments, the pharmaceutical composition further comprises:
(g) a lubricant.

In some embodiments, the pharmaceutical composition comprises:
(a) about 3%to about 30%by weight of a compound of formula (I)

or a pharmaceutically acceptable salt thereof;
(b) about 15%to about 70%by weight of a filler (c) about 10%to about 45%by weight of a
first polymeric release-controlling agent,
(d) 0%to about 20%by weight of a second polymeric release-controlling agent,
(e) 0%to about 40%by weight of an acidulant,
(f) 0%to about 2%by weight of a glidant, and
(g) 0%to about 2%by weight of a lubricant,
based on the total weight of the pharmaceutical composition;
wherein the first polymeric release-controlling agent has a viscosity of about 80 to about 120 mPa·s.

In some embodiments, the first polymeric release-controlling agent is HPMC with a viscosity of about 80 to about 120 mPa·s; preferably, the first polymeric release-controlling agent is HPMC K100 LV; more preferably, the first polymeric release-controlling agent is HPMC K100 Premium LV DC2.

In some embodiments, the filler is selected from one or more of microcrystalline cellulose, lactose, dibasic calcium phosphate and sorbitol; preferably, the filler is selected from one or two of microcrystalline cellulose and lactose; more preferably, the filler is lactose.

In some embodiments, the microcrystalline cellulose is microcrystalline cellulose PH-102.

In some embodiments, the lactose is selected from one or two of lactose monohydrate and anhydrous lactose; preferably, the lactose is lactose monohydrate; more preferably, the lactose is lactose monohydrate 316.

In some embodiments, the second polymeric release-controlling agent is selected from one or more of HPMC with a viscosity of about 3000 to about 5600 or mPa·s, HPMC with a viscosity of about 40 to about 60 mPa·s, and Eudragit with a viscosity of about 100 to about 200 mPa·s; preferably, the second polymeric release-controlling agent is selected from one or more of HPMC K4M, HPMC E50LV, and Eudragit L100-55; more preferably, the second polymeric release-controlling agent is HPMC K4M.

In some embodiments, the HPMC K100 LV is selected from one or more of HPMC K100 Premium LV, HPMC K100 Premium LV CR, and HPMC K100 Premium LV DC2;
preferably, the HPMC K100 LV is HPMC K100 Premium LV DC2.

In some embodiments, the HPMC K4M is selected from HPMC K4M Premium LV and HPMC K4M Premium CR; preferably, the HPMC K4M is HPMC K4M Premium CR.

In some embodiments, the acidulant is selected from one or more of tartaric acid, fumaric acid and succinic acid; preferably, the acidulant is tartaric acid, or tartaric acid and fumaric acid; more preferably, the acidulant is tartaric acid and fumaric acid.

In some embodiments, the tartaric acid is L-tartaric acid (+) .

In some embodiments, the glidant is colloidal silicon dioxide.

In some embodiments, the colloidal silicon dioxide is colloidal silicon dioxide Aerosil 200 Pharma.

In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the magnesium stearate is magnesium stearate LIGAMED MF-2-V.

In some embodiments, the pharmaceutical composition comprises about 6%to about 15.2%by weight of the compound of formula (I) .

In some embodiments, the pharmaceutical composition comprises about 21.5%to about 64%by weight of the filler.

In some embodiments, the pharmaceutical composition comprises about 15%to about 40%by weight of the first polymeric release-controlling agent; preferably, the pharmaceutical composition comprises about 25%to about 40%by weight of the first polymeric release-controlling agent; more preferably, the pharmaceutical composition comprises about 30%to about 40%by weight of the first polymeric release-controlling agent.

In some embodiments, the pharmaceutical composition comprises about 0%to about 15%by weight of the second polymeric release-controlling agent.

In some embodiments, the pharmaceutical composition comprises about 15%to about 35%by weight of the acidulant; preferably, the pharmaceutical composition comprises about 15%to about 30%by weight of the acidulant.

In some embodiments, the pharmaceutical composition comprises about 0%to about 30%by weight of the tartaric acid; preferably, the pharmaceutical composition comprises about 15%to about 30%by weight of the tartaric acid; more preferably, the pharmaceutical composition comprises about 20%by weight of the tartaric acid.

In some embodiments, the pharmaceutical composition comprises about 0%to about 20%by weight of the fumaric acid; preferably, the pharmaceutical composition comprises about 10%to about 20%by weight of the fumaric acid; more preferably, the pharmaceutical composition comprises about 10%by weight of the fumaric acid.

In some embodiments, the pharmaceutical composition comprises preferably about 15%by weight of the tartaric acid, or about 20%by weight of the tartaric acid and about 10%by weight of the fumaric acid; more preferably, the pharmaceutical composition comprises about 20%by weight of the tartaric acid and about 10%by weight of the fumaric acid.

In some embodiments, the pharmaceutical composition comprises about 0%to about 1%by weight of the glidant; preferably, the pharmaceutical composition comprises about 0.5%to about 1%by weight of the glidant; more preferably, the pharmaceutical composition comprises about 1%by weight of the glidant.

In some embodiments, the pharmaceutical composition comprises about 1%to about 1.5%by weight of the lubricant.

In some embodiments, the first polymer carrier and the compound of formula (I) have a mass ratio of about (1～7) : 1.

In some embodiments, when the first polymer carrier and the compound of formula (I) have a mass ratio of <1.5: 1, the pharmaceutical composition comprises preferably the second polymeric release-controlling agent. The second polymeric release-controlling agent is preferably HPMC K4M. The second polymer carrier and the compound of formula (I) have a mass ratio of about (0.3～1.5) : 1, preferably about (0.3～1) : 1.

In some embodiments, when the first polymer carrier and the compound of formula (I) have a mass ratio of about (1.5～7) : 1, the second polymeric release-controlling agent is preferably selected from one or two of HPMC E50LV and Eudragit L100-55.

In some embodiments, when the first polymer carrier and the compound of formula (I) have a mass ratio of about (1.5～7) : 1, the pharmaceutical composition comprises preferably the acidulant. The acidulant and the compound of formula (I) have a mass ratio of (1～5) : 1, for example 1: 1, 1.25: 1, 2: 1, 2.3: 1, 2.5: 1 or 5: 1.

In some embodiments, when the acidulant is the tartaric acid and the fumaric acid, the tartaric acid and the fumaric acid have a mass ratio of about (0.75～2) : 1, for example 0.75: 1, 1: 1 or 2:1, preferably 2: 1.

In some embodiments, in the pharmaceutical composition, the compound of formula (I) has a mass of about 20 mg to about 80 mg, for example, about 20, 30, 40, 60 or 80 mg; preferably, the compound of formula (I) has a mass of about 20 mg to about 60 mg; more preferably, the compound of formula (I) has a mass of about 20 mg to about 40 mg.

In some embodiments, the pharmaceutical composition has a mass of about 200 mg to about 400 mg, for example, about 266 mg or about 333 mg; preferably, the pharmaceutical composition has a mass of about 300 mg to about 400 mg, for example, about 333 mg.

In some embodiments, the pharmaceutical composition comprises:
(a) a compound of formula (I)

or a pharmaceutically acceptable salt thereof;
(b) a filler;
(c) a first polymeric release-controlling agent;
(d) optionally, a second polymeric release-controlling agent;
(e) optionally, an acidulant;
(f) optionally, a glidant; and
(g) optionally, a lubricant;
wherein the first polymeric release-controlling agent has a viscosity of 80 to 120 mPa·s.

In some embodiments, the pharmaceutical composition comprises components shown in any one of the following schemes,

scheme 1: about 15.2%by weight of the compound of formula (I) , about 53.8%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 2: about 15%by weight of the compound of formula (I) , about 54%by weight of lactose monohydrate, about 15%by weight of HPMC K100 LV, about 15%by weight of HPMC K4M, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 3: about 15%by weight of the compound of formula (I) , about 54%by weight of lactose monohydrate, about 25%by weight of HPMC K100 LV, about 5%by weight of HPMC K4M, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 4: about 15%by weight of the compound of formula (I) , about 64%by weight of lactose monohydrate, about 20%by weight of HPMC K100 LV, about 15%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 5: about 15%by weight of the compound of formula (I) , about 39%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 15%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 6: about 15%by weight of the compound of formula (I) , about 29%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 10%by weight of Eudragit L100-55, about 15%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 7: about 15%by weight of the compound of formula (I) , about 39%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 8: about 15%by weight of the compound of formula (I) , about 24%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 30%by weight of tartaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 9: about 15%by weight of the compound of formula (I) , about 24%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 15%by weight of HPMC E50LV, about 15%by weight of tartaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 10: about 15%by weight of the compound of formula (I) , about 34%by weight of lactose monohydrate, about 20%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 11: about 15%by weight of the compound of formula (I) , about 24%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 12: about 15%by weight of the compound of formula (I) , about 29%by weight of lactose monohydrate, about 25%by weight of HPMC K100 LV, 15%by weight of tartaric acid, about 15%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 13: about 15%by weight of the compound of formula (I) , about 24%by weight of lactose monohydrate, about 25%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, about 20%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 14: about 15%by weight of the compound of formula (I) , about 20%by weight of lactose monohydrate, about 19%by weight of microcrystalline cellulose, about 30%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 15: about 15%by weight of the compound of formula (I) , about 20%by weight of lactose monohydrate, about 19%by weight of dicalcium phosphate, about 30%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 16: about 15%by weight of the compound of formula (I) , about 23.5%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 0.5%by weight of colloidal silicon dioxide, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 17: about 12%by weight of the compound of formula (I) , about 26%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 0.5%by weight of colloidal silicon dioxide, and about 1.5%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 18: about 12%by weight of the compound of formula (I) , about 41%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, about 0.5%by weight of colloidal silicon dioxide, and about 1.5%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 19: about 9%by weight of the compound of formula (I) , about 23%by weight of lactose monohydrate, about 35%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 1%by weight of colloidal silicon dioxide, and about 2%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 20: about 9%by weight of the compound of formula (I) , about 23%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 5%by weight of HPMC K4M, 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 1%by weight of colloidal silicon dioxide, and about 2%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 21: about 12%by weight of the compound of formula (I) , about 25%by weight of lactose monohydrate, about 35%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 1%by weight of colloidal silicon dioxide, and about 2%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 22: about 15%by weight of the compound of formula (I) , about 58%by weight of dicalcium phosphate, about 20%by weight of microcrystalline cellulose, about 6%by weight of Carbopol 71GN, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 23: about 15%by weight of the compound of formula (I) , about 54%by weight of lactose monohydrate, about 13.5%by weight of HPMC K100 LV, about 16.5%by weight of HPMC K4M, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 24: about 15%by weight of the compound of formula (I) , about 33.5%by weight of lactose monohydrate, about 20%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 0.5%by weight of colloidal silicon dioxide, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 25: about 15%by weight of the compound of formula (I) , about 23.5%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 15%by weight of HPMC E50LV, about 20%by weight of tartaric acid, about 0.5%by weight of colloidal silicon dioxide, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 26: about 12%by weight of the compound of formula (I) , about 25.5%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 1%by weight of colloidal silicon dioxide, and about 1.5%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 27: about 6%by weight of the compound of formula (I) , about 21.5%by weight of lactose monohydrate, about 40%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 1%by weight of colloidal silicon dioxide, and about 1.5%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition.

In some embodiments, the compound of formula (I) in any one of the schemes 1-24 is preferably the crystalline form B.

In some embodiments, the microcrystalline cellulose in any one of the schemes 14 and 22 is preferably Microcrystalline Cellulose PH-102.

In some embodiments, the colloidal silicon dioxide in any one of the schemes 16-21 and 24-27 is preferably Colloidal Silicon Dioxide Aerosil 200 Pharma.

In some embodiments, the magnesium stearate in any one of the schemes 1-27 is preferably Magnesium Stearate Ligamed MF-2-V.

In some embodiments, the HPMC K4M in any one of the schemes 2-3, 20 and 23 is preferably HPMC K4M Premium CR.

In some embodiments, the HPMC K100 LV in any one of the schemes 1-21 and 23-27 is preferably HPMC K100 Premium LV DC2. In some embodiments, the tartaric acid in any one of the schemes 7-21 and 24-27 is preferably L-Tartaric acid (+) /crystal.

In some embodiments, the lactose monohydrate in any one of the schemes 1-21 and 23-27 is preferably Lactose Monohydrate 316.

In some embodiments, the dicalcium phosphate in any one of the schemes 15 and 22 is preferably Dicalcium Phosphate Dihydrate.

In some embodiments, the pharmaceutical composition comprises preferably the components shown in any one of the schemes 1-3, 5-9, 11-18 and 25-27, more preferably the schemes 3, 5-9, 11-18, and 26-27.

In some embodiments, the pharmaceutical composition is composed of the components shown in any one of the schemes 1-27.

In some embodiments, the pharmaceutical composition is preferably composed of the components shown in any one of the schemes 1-3, 5-9, 11-18 and 25-27, more preferably the schemes 3, 5-9, 11-18, and 26-27.

In some embodiments, the dosage form is a solid dosage form in the form of a tablet.

In some embodiments, the tablet is coated.

In some embodiments, the pharmaceutical composition is used for inhibiting JAK (e.g., JAK1) .

In some embodiments, the pharmaceutical composition is used for treating JAK (e.g., JAK1) -mediated disease or disorder.

In some embodiments, the unit dosage form comprises about 20 mg to about 80 mg, preferably about 20 mg to about 60 mg, more preferably about 20 mg to about 40 mg, of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition has a mass of about 200 mg to about 400 mg, preferably, about 300 mg to about 400 mg.

In some embodiments, the disease or disorder is an inflammatory disease, an autoimmune disease, an immune-mediated disease, or cancer.

In some embodiments, the JAK1-mediated disease or disorder is selected from asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) , juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease) , endocrinopathies (e.g., type 1 diabetes and Graves’ disease) , neurodegenerative diseases (e.g., multiple sclerosis (MS) ) , autistic spectrum disorder, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, amyotrophic lateral sclerosis (ALS) , Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CID) , vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis) , skin diseases (e.g., acne vulgaris dermatomyositis, pemphigus, systemic lupus erythematosus (SLE) , discoid lupus erthematosus, scleroderma, psoriasis, plaque psoriasis, vasculitics, vitiligo and alopecias) , Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS) , celiac disease, pemphigus, transplant rejection (allograft transplant rejection) , graft-versus-host disease (GVDH) , an inflammatory disease, an autoimmune disease, an immune-mediated disease, cancer, rheumatoid arthritis, ankylosing spondylitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn’s , ulcerative colitis, DES, vitiligo, alopecia areata, and alopecia totalis.

In some embodiments, the process for preparing the pharmaceutical composition further comprises:
(d) compressing the pharmaceutical composition into a tablet.

In some embodiments, the process for preparing the pharmaceutical composition further comprises:
(e) coating the tablet with a non-functional coating made of compendial excipients or a
functional coating made of compendial excipients.

The present disclosure further provides a pharmaceutical composition, wherein the pharmaceutical composition is prepared by a process for preparing the pharmaceutical composition as described herein, comprising:
(a) blending the compound of formula (I) and the filler to obtain a first blend;
(b) blending the first blend with the first polymeric release-controlling agent, optionally the
second polymeric release-controlling agent, optionally the acidulant, and optionally the glidant to obtain a second blend; and
(c) blending the second blend with the lubricant to obtain the pharmaceutical composition.

The present disclosure further provides a pharmaceutical composition comprising the following components: 9.6%by weight of the compound of formula (I) , 32.2%by weight of Mannitol 100 SD, 20%by weight of Pregelatinized starch, 32.2%by weight of Microcrystalline cellulose PH-102, 3%by weight of Croscarmellose sodium SD-711, 2%by weight of Magnesium stearate Ligamed MF-2-V, and 1%by weight of Colloidal silicon dioxide 200 Pharma; based on the total weight of the pharmaceutical composition; the pharmaceutical composition is preferably immediate release (IR) capsule formulation.

The present disclosure further provides a method for treating a disease or disorder in a subject in need thereof, comprising administering an effective amount of a pharmaceutical composition as described herein to the subject.

The present disclosure further provides the pharmaceutical composition as described herein for use in treating a disease or disorder.

The present disclosure further provides use of the pharmaceutical composition as described herein in the manufacture of a medicament for treating a disease or disorder.

In some embodiments, the disease or disorder is JAK (e.g., JAK1) -mediated disease or disorder.

In some embodiments, the JAK (e.g., JAK1) -mediated disease or disorder is selected from one or more of an inflammatory disease, autoimmune disease, immune-mediated disease, and cancer.

In some embodiments, the autoimmune disease may be, for example, atopic dermatitis, rheumatoid arthritis, or ankylosing spondylitis.

The following examples are meant to be illustrative of the practice of the invention and not limiting in any way.
Examples

Unless otherwise specified, the material name and sources corresponding to the components in the formulations of the following examples are shown in the table below:

Unless otherwise specified, the two-stage test method used in the following examples is shown in the table below:

Unless otherwise specified, the release test method used in the following examples is shown in the table below:

Example 1. Crystalline Form B of the Compound of Formula (I)
Preparation of The Crystalline Form B

The structure of compound of formula (I) :

which was prepared according to the method described in page sixty of example 1 in patent WO
2020/088659 A1 (PCT/CN2019/115069, filed November 1, 2019, priority date November 1, 2018, incorporated herein by reference in its entirety) . It was used as the starting material in the preparation of crystalline form B.
Representative preparation method of crystalline form B

16.2 kg acetone, 5.2 kg purified water and 2.05 kg starting material were added into reactor R1 in turn. After that, stirring was started and the reactor was heated to 50～60 ℃. After the material was completely dissolved, the reactor was kept warm and stirred for 0.5～1 hour. The material liquid in reactor R1 was filtered through a precision filter and transferred to reactor R2 until no liquid droplets came out. Subsequently, 1.6 kg acetone and 0.6 kg purified water were added to rinse reactor R1 and the resulting solution was filtered through the precision filter to reactor R2. The internal temperature of R2 was controlled at 45～50 ℃ and 39.6 kg purified water was dropped into the reactor through a high-level tank. After the dropping, the temperature in the reactor was controlled at 45-50℃ and maintained for 0.5-1 hour. The reactor R2 was slowly cooled down to an internal temperature of 30-40℃ and the temperature was maintained for 1-2 hours. The reactor R2 was further cooled down until the internal temperature was around 15-25℃and the temperature was maintained for 10-16 hours. The material in the reactor R2 is filtered through a filter. 10.4 kg purified water was used to wash the reactor and the resulting solution was filtered to wash the filter cake until almost no liquid drops flowed out. The wet product was taken out, transferred to a vacuum oven and dried in vacuum for 12～36 hours to obtain crystalline form B. HPLC purity: 99.55%, yield: 82.7%.

The crystalline form B was characterized by XRPD and proton nuclear magnetic resonance (¹H NMR) . The results indicated the form is an anhydrate.
Characteristics of The Crystalline Form B

XRPD pattern of the crystalline form B is obtained with following parameters:

The XRPD pattern of the crystalline form B is shown in FIG. 1.

The XRPD pattern of the crystalline form B has characteristic diffraction peaks at the 2θangles as shown in Table 1.
Table 1. Characteristic XRPD peaks

SCXRD of The Crystalline Form B

The SCXRD characterization of the crystalline form B indicated that it crystalizes as a triclinic crystal system and in thespace group. The unit cell parameters are α=83.7635 (5) °, β=89.7471 (4) °, γ=80.2878 (5) °, and The asymmetric unit of the single crystal structure is comprised of only one molecule of the compound of formula (I) , confirming that the crystalline form B is an anhydrate. Additional crystallographic data and refinement parameters are summarized in Table 2.
Table 2. Crystallographic data and refinement parameters of Form B single crystal

The single crystal sample was obtained by adding 31.8 mg of the starting material into a 3 mL glass vial with 1.0 mL ethanol/water (70/30, v/v) . After being shaken, the suspension was equilibrated at 50 ℃ for 2 hours, followed by filtration via a 0.45μm PTFE filter. The clear filtrate was placed in a new clean 3 mL vial (the filter membrane and 3 mL vial were pre-heated at 50 ℃) . The vial was sealed with a cap and placed in a 50 ℃ biochemical incubator for slow cooling (50 ℃to 5 ℃ cooling at 0.1 ℃/min) . The vial was cooled to -20 ℃ for 4 hours. The solution was filtered to a new clean 3 mL vial then sealed withM Film with 8 pinholes on it for slow evaporation at RT. After 4 days of slow evaporation, a crystal sample was obtained in the mother liquid. XRPD characterization showed the obtained crystal was the Form A polymorph. The 3 mL vial was then sealed by cap and stored at RT for another 50 days, and the XRPD characterization showed the Form A had changed to the Form B.

An XRPD pattern generated from the Form B single crystal XRD data is consistent with the experimental XRPD patterns of the Form B single crystal sample.

Unless otherwise specified, the active pharmaceutical ingredient (API) used in the following examples refers to the crystalline form B of the compound of formula (I) .
Example 2. Exemplary pharmaceutical compositions and dosage forms

The exemplary pharmaceutical compositions and dosage forms described in this application are offered to illustrate embodiments of the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. For example, an excipient may act with a one or more similar or various functions (e.g., filler, glidant, disintegrant, etc. ) and identification of a particular function herein is not to be construed in any way as limiting the scope of the respective component.

Table 3 shows an exemplary immediate release (IR) capsule formulation comprising the API, and the IR formulation is prepared by the following steps.

Step 1: Micronization of API

Use a jet mill to micronize API.

Step 2: Premix and sieve

Weigh the raw materials and excipients and pass some mannitol through a 30-mesh sieve, then mix with API manually for 20 turns, pass through a 30-mesh sieve, add the remaining mannitol, and mix manually for 20 Circles; croscarmellose sodium and colloidal silicon dioxide are mixed manually for 20 circles and passed through a 30-mesh sieve.

Step 3: Mix

Add the mixture of microcrystalline cellulose, mannitol and API, pregelatinized starch, croscarmellose sodium and colloidal silicon dioxide to the mixing barrel in sequence, and mix

Step 4: Dry Granulation

Transfer the mixed powder to the dry granulator, set the pressure of the pressure wheel to 5.0 MPa, and granulate at a speed of 60 rpm.

Step 5: Lubricate

Pass magnesium stearate through a 30-mesh sieve. Add the granules prepared in step 4 and magnesium stearate to a mixer in sequence and mix at 20 rpm for 4 minutes.

Step 6: Capsule filling

Use a fully automatic capsule filling machine to put the above mixture into an empty capsule shell.
Table 3. Exemplary IR formulation comprising 12 mg of the API

Also disclosed herein are exemplary extended release (ER) tablet formulations comprising the API. In certain embodiments, the ER tablet formulations comprising the API provide certain advantages over the IR formulations such as, but not limited to, exhibiting improved compatibility of the selected excipients and the API to produce desirable in vitro and/or in vivo dissolution profiles, lower pill burden, desirable processing properties such as ease of handling, ease of processing, storage stability, and ease of purification, and improved shelf-life and favorable storage conditions.

Unless otherwise specified, the ER tablet formulations comprising the API in the examples are prepared by the following steps.

Step 1: all ingredients were sieved through a 600μm sieve prior to blending for depumping purposes.

Step 2: lactose was added to the blender, followed by the API, where the bag was rinsed with a small amount of lactose and transferred to the blender, and blended for 11 minutes at 29 RPM.

Step 3: the polymer (s) , acidulant (s) , and glidant were added to the blender and blended for 11 minutes at 29 RPM.

Step 4: the lubricant was passed through 600μm sieve and added to the blender and blended for 2 minutes at 29 RPM.

Step 5: the blend was compressed at target weight and hardness.

An exemplary process utilized preblend, rinse and final blending followed by lubrication step (FIG. 2) .

The tablet formulations may be coated with a non-functional coating made of compendial excipients or a functional coating made of compendial excipients, for example, a film coating premix coating liquid (88A130051-CN) with a 20%solid content was prepared, and the tablet was coated on the Vector coating machine with a coating weight of 8%.
Polymer Types

Table 4 shows exemplary prototype formulations to determine the appropriate polymer grade and amount to include in the formulation.
Table 4. Exemplary prototype formulations to evaluate HPMC grade and level

A two-stage test was performed on each of the above formulations. Dissolution profiles are shown in FIG. 3. Although total HPMC concentration was 30%w/w for both formulations, ER2 and ER3 resulted in very different dissolution profiles depending on the amount HPMC K4M used in combination with HPMC K100 LV.
Acidulants

Based at least on the results from the polymer types, it was observed that dissolution rate started to slow down or show inflection on the curve when the pH was switched to pH 6.8 (approximately 1 hr to 8 hrs) . One or more acidulants were added to the formulation to improve the solubility and therefore dissolution rate after changing to pH 6.8. Exemplary formulations comprising fumaric acid are presented in Table 5.
Table 5. Formulations comprising fumaric acid

A two-stage test was performed on each of the above formulations. The resulting dissolution profiles are shown in FIG. 4. Compared to a control (formulation that did not contain any acidulant, ER1) , inclusion of fumaric acid improved the rate of solubility at each time point in pH 6.8 as shown in FIG. 5. However, addition of fumaric acid did not result in a linear increase.

Tartaric acid was used to determine whether an improved release rate could be achieved by increasing linearity and minimizing or eliminating the inflection of the release curve. Exemplary formulations comprising tartaric acid are presented in Table 6.
Table 6. Formulations comprising tartaric acid

A two-stage test was performed on each of the above formulations. The resulting dissolution profiles are presented in FIG. 6. The inflection of the curve was eliminated when tartaric acid was used in place of fumaric acid or no acidulant (e.g., ER7 vs ER5 and ER1, respectively) , minimizing the impact on release due to pH change. FIG. 7 shows that there was an improvement in the dissolution rate at each time point after switching to pH 6.8 with the inclusion of tartaric acid compared to a formulation that did not contain any acidulant with 30%HPMC K100 LV (e.g., ER1 vs ER7) . However, in the presence of only tartaric acid, a slightly slower release rate was observed at each time point compared to formulations containing fumaric acid as shown in FIG. 8.

Exemplary formulations comprising both tartaric acid and fumaric acid were prepared according to Table 7. HPMC K100 LV concentration was varied between 20 and 30%w/w, fumaric acid concentration between 10 and 20%w/w, and tartaric acid concentration between 15 and 20%w/w.
Table 7. Exemplary formulations comprising both acidulants

A two-stage test was performed on each of the above formulations. The resulting dissolution profiles are presented in FIG. 9. Overall, all 4 formulations yielded well-controlled rate of dissolution with no obvious inflection of the curve showing the effect of pH shift. There was no observable difference in dissolution with fumaric acid between 15%w/w and 20%w/w when tartaric acid was held constant at 15%w/w (ER12 and ER13) as seen in FIG. 10. As shown in FIG. 11, acidulants improved overall drug solubility.
Fillers

Microcrystalline cellulose (MCC) , dicalcium phosphate, and lactose monohydrate were evaluated as fillers to determine the filler impact in compression or dissolution. Table 8 shows exemplary formulations comprising different fillers.
Table 8. Formulations comprising filler combinations

HPMC = Hydroxypropyl methyl cellulose.

A two-stage test was performed on each of the above formulations. The resulting dissolution profiles are presented in FIG. 12. Based on the dissolution profiles, the formulation containing dicalcium phosphate (ER15) resulted in lower drug release at all time points including after the full 24 hrs while there was no visually significant difference in the profiles of formulations containing lactose monohydrate vs 1: 1 ratio of lactose monohydrate and MCC (ER7 vs ER14) .
Tablet weight

Exemplary prototype formulations of varying weights as shown in Table 9 were tested to determine the effect of tablet weight on dissolution profiles.
Table 9. Exemplary formulations of varying tablet weight

A two-stage test was performed on each of the above formulations. The resulting dissolution profiles are in FIG. 13. There were marked differences in the profiles when the tablet composition was kept the same but made larger in size. Surprisingly, ER17 also yielded similar profile as ER18 with just one acidulant, tartaric acid.
API weight

Exemplary prototype formulations of another API weight as shown in Table 10 were tested to determine the effect of API weight on dissolution profiles.
Table 10. Exemplary formulations of another API weight

A two-stage test was performed on each of the above formulations. The resulting dissolution profiles are in FIG. 14. Surprisingly, formulations comprising 30 mg API and the proportional formulation comprising 60 mg API yielded similar profile as the formulation with 40 mg of API (ER26) .
Example 3. In-vivo performance of exemplary ER tablets (dogs)

In this study, four exemplary ER tablet formulations according to Tables 11-14 were administered to dogs. The formulation of Table 11, based on 15%w/w HPMC K100 LV and 15%HPMC K4M gave dissolution results of 80%released around 9 hours (oval-shaped tablets) . The second formulation of Table 12, based on 25%w/w HPMC K100 LV and 5%w/w HPMC K4M gave a more rapid dissolution of 80%released at 6 hours and 90%around 7 hours (oval-shaped tablets) . The third formulation of Table 13, based on a matrix of 6%w/w Carbopol 71GNF (ER22) gave a dissolution of 80%released at 10 hours (oval-shaped tablets) . The fourth formulation of Table 14 was made using API with a matrix comprised of 13.5%w/w HPMC K100 LV and 16.5%w/w HPMC K4M (ER23) gave an 80%release at 10 hours.
Table 11. An exemplary ER formulation (ER2)

Table 12. An exemplary ER formulation (ER3)

Table 13. An exemplary ER formulation (ER22)

Table 14. An exemplary ER formulation (ER23)

Example 4. In-vivo performance of exemplary ER tablets (humans)

In this study, small cohorts of healthy human volunteers (n=4) were used to determine the human PK profile for the exemplary formulations comprising the API as shown in Table 15. The volunteers received the oral formulation in a crossover fashion: 36 mg (3 x 12 mg) IR capsule formulation of Table 3 (fasted) on Day 1, followed by a 40 mg ER tablet formulation according to Table 15 (fasted) on Day 3.
Table 15. Exemplary batch formulations for evaluating in-vivo performance

A two-stage test was performed on each of the above formulations. The resulting dissolution profiles are presented in Table 16 and FIG. 15.
Table 16. Dissolution over 24 hours for exemplary formulations

Each of the dissolution profiles exhibited smoother profiles with no obvious inflection point during the pH change to 6.8. The grade and amount of polymer, combination of acidulants, amount of soluble filler (e.g., lactose) impacted the specific profile of each formulation.

A release test method was used to evaluate dissolution over 6.5 hours (Table 17 and FIG. 16) .
Table 17. Dissolution over 6.5 hours for exemplary formulations (ER24, ER16, ER25, ER3, ER18
and ER17)

The PK results obtained during the in-vivo study is summarized in Table 18. FIG. 17 shows a semi-log plot of the C-T profile for cohorts 1-6 (C1 to C6) for the ER formulations in comparison with the IR formulation.
Table 18. PK results of exemplary formulations in the in-vivo study

Formulations ER25, ER18 and ER17 were preferred from a PK perspective based on sustained release and reduced C_max with resulting lower C_max/AUC ratio. However, formulation ER25 exhibited lower bioavailability and thus to achieve a desired exposure (AUC) , it would require increasing the dose to 60 mg. Formulations ER18 and ER17 were similar with respect to their PK properties. The inclusion of fumaric acid in formulation ER17 as compared to formulation ER18 increased T_max and prolonged release/exposure.

Table 19 summarizes mean PK parameters to evaluate variability of the exemplary formulations. Formulations ER18 and ER17 (Cohorts 5 and 6) demonstrated reduced variability compared to other ER formulations.
Table 19. Mean (%CV) PK parameters of the exemplary ER formulations

*Assuming dose proportionality, mean profiles of ER25, and ER3 were dose adjusted to 60 mg.

The exemplary formulations were also tested in vitro (two-stage test) . As shown in FIG. 18, acidulants smoothed release; tartaric acid controlled low pH release; fumaric acid boosted high pH release; decreasing polymer content increased release; and decreasing drug load slowed release. In FIG. 18, numbers 1-6 corresponded to ER24, ER16, ER25, ER3, ER18, and ER17 as shown in Table 15, respectively.

Table 20 outlines the dissolution profiles in two-stage test method and release test method for ER17 and profiles are graphed in FIG. 19. Table 21 outlines the stability results for ER17.
Table 20. Dissolution results for ER17

Table 21. Stability results for ER17

Formulation ER17 resulted in less-than-optimal powder flow along with some tablets showing sticking during compression process. To improve powder flow and resolve sticking, glidant (e.g., colloidal silicon dioxide) may be increased from 0.5%w/w to 1.0%w/w. In addition, a moisture barrier immediate release tablet film coating may control the appearance change (mottled) as seen earlier with the use of tartaric acid.
Another exemplary ER tablet formulation comprising 40 mg of API is shown in Table 22.
Table 22. Exemplary tablet formulation comprising 40 mg of API (Formulation ER26)

An exemplary tablet formulation comprising 20 mg of API is shown in Table 23. FIG. 20 shows the dissolution profile in comparison with ER26 comprising 40 mg of the API.
Table 23. Exemplary tablet formulation comprising 20 mg of API (Formulation ER27)

FIG. 21 shows the comparison of mean C-T profiles of ER27 (20 mg dose, cohort 8) , ER26 (40 mg dose, cohort 6, formulation 55’ ) , and two ER26 (80 mg dose, cohort 7) . As in cohort 6, four healthy volunteers in cohorts 7-8 were administered the API in a crossover fashion: 36 mg (3 x 12 mg) IR formulation (fasted) on Day 1, followed by ER27 according to Table 23 or two ER26 according to Table 22 (fasted) on Day 3. Table 24 summarizes the PK data of the exemplary formulations. The 20 mg ER formulation demonstrated a slower and more sustained release of API compared to the IR formulation, with a similar profile shape as formulations at dose levels of 40 mg and 80 mg. Exposures of the 20 mg formulation appeared to approximately dose proportional compared to 40 mg formulation.
Table 24. Summary of PK data for exemplary ER/IR formulations

*Assuming linearity C_max and AUC values for IR formulation were dose adjusted to 20 mg; T_max
expressed as median (min, max) .
Example 5. In-vivo performance of exemplary ER tablet and upadacitinib ER formulation
(dogs)

In this study, Beagle Dogs (n=4) were used to determine the dog PK profiles of Upadacitinib ER tablet (15mg) . Blood samples were taken after 0.25, 0.5, 1, 2, 4, 8, 16 and 24 hours after administration. ER19 containing 30 mg of the API was administered to 3 dogs to obtain the dog PK profile of ER19 (30 mg) . Blood samples were taken after 0.25, 0.5, 0.75, 1, 2, 4, 8, 12 and 24 hours after administration. And the ER19 -adjusted to 15mg profile is projected from the ER (30mg) profile.
Table 25. Upadacitinib ER formulation

Upadacitinib PK analytical method
General sample processing procedure (Plasma) :

Protein precipitation (PPT) using 96-well plate
1) An aliquot of 20 μL unknown sample, calibration standard, quality control and dilution quality
control (if have) , single blank, and double blank sample was added to the 96-well plate respectively;
2) Each sample (except the double blank) was quenched with 400 μL of IS1 respectively (double
blank sample was quenched with 400 μL of ACN) , and then the mixture was vortex-mixed for 10 min at 800 rpm and centrifuged for 15 min at 3220 × g, 4 ℃;
3) An aliquot of 50 μL supernatant was transferred to another clean 96-well plate and centrifuged for
5 min at 3220 × g, 4 ℃, then the supernatant was directly injected for LC-MS/MS analysis.

ER19 dog PK analytical method

Table 26 and FIG. 22 compared the PK profiles of Upadacitinib ER (15mg) and ER19 (adjusted to 15mg) . Compared to dogs received Upadacitinib ER, the Dogs administrated ER19 have higher AUC and prolonged release.
Table 26. Summary of PK data for exemplary ER formulations and Upadacitinib ER formulation

Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment, ” “an embodiment, ” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment, ” “in an embodiment, ” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and/or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.
Incorporation by Reference

References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.
Equivalents

The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

A pharmaceutical composition, comprising:

(a) a compound of formula (I)

or a pharmaceutically acceptable salt thereof;

(b) a filler; and

(c) a first polymeric releasing-controlling excipient,

wherein the first polymeric release-controlling agent has a viscosity of about 80 to about 120 mPa·s.
The pharmaceutical composition according to claim 1, further comprising:

(d) a second polymeric release-controlling excipient;

(e) an acidulant;

(f) a glidant; and/or

(g) a lubricant.
The pharmaceutical composition according to claim 1 or 2, wherein (a) the compound of formula (I) , or a pharmaceutically acceptable salt thereof, is in crystalline form B having an X-ray powder diffraction (XRPD) pattern comprising characteristic diffraction peaks at the following 2θ angles: 10.815°±0.2°, 13.475°±0.2°, 17.225°±0.2°, 21.804°±0.2°, and 22.361°±0.2°, with a radiation source of Cu-Kα; optionally, the XRPD pattern further comprises one or more characteristic diffraction peaks at the following 2θ angles: 9.959°±0.2°, 11.757°±0.2°, 14.974°±0.2°, 20.481°±0.2°, 21.033°±0.2°, 21.544°±0.2°, 23.462°±0.2°, 23.687°±0.2°, 25.155°±0.2°, 29.747°±0.2°, 30.292°±0.2°, and 38.075°±0.2°, with a radiation source of Cu-Kα; preferably, the XRPD pattern having characteristic diffraction peaks at the following 2θ angles: 9.959°±0.2°, 10.815°±0.2°, 11.757°±0.2°, 13.475°±0.2°, 14.974°±0.2°, 17.225°±0.2°, 20.481°±0.2°, 21.033°±0.2°, 21.544°±0.2°, 21.804°±0.2°, 22.361°±0.2°, 23.462°±0.2°, 23.687°±0.2°, 25.155°±0.2°, 29.747°±0.2°, 30.292°±0.2°, and 38.075°±0.2°, with a radiation source of Cu-Kα; optionally, the XRPD pattern further comprises one or more characteristic diffraction peaks at the following 2θ angles: 10.092°±0.2°, 13.198°±0.2°, 16.360°±0.2°, 16.784°±0.2°, 17.918°±0.2°, 18.347°±0.2°, 19.243°±0.2°, 20.062°±0.2°, 22.774°±0.2°, 24.153°±0.2°, 24.906°±0.2°, 26.188°±0.2°, 26.697°±0.2°, 27.787°±0.2°, 28.192°±0.2°, 30.957°±0.2°, 31.486°±0.2°, 32.819°±0.2°, 32.973°±0.2°, 33.579°±0.2°, 34.573°±0.2°, 34.939°±0.2°, 35.947°±0.2°, 36.722°±0.2°, 36.954°±0.2°, 39.153°±0.2°, and 39.714°±0.2°, with a radiation source of Cu-Kα; more preferably, the XRPD pattern having characteristic diffraction peaks at the following 2θ angles: 9.959°±0.2°, 10.092°±0.2°, 10.815°±0.2°, 11.757°±0.2°, 13.198°±0.2°, 13.475°±0.2°, 14.974°±0.2°, 16.360°±0.2°, 16.784°±0.2°, 17.225°±0.2°, 17.918°±0.2°, 18.347°±0.2°, 19.243°±0.2°, 20.062°±0.2°, 20.481°±0.2°, 21.033°±0.2°, 21.544°±0.2°, 21.804°±0.2°, 22.361°±0.2°, 22.774°±0.2°, 23.462°±0.2°, 23.687°±0.2°, 24.153°±0.2°, 24.906°±0.2°, 25.155°±0.2°, 26.188°±0.2°, 26.697°±0.2°, 27.787°±0.2°, 28.192°±0.2°, 29.747°±0.2°, 30.292°±0.2°, 30.957°±0.2°, 31.486°±0.2°, 32.819°±0.2°, 32.973°±0.2°, 33.579°±0.2°, 34.573°±0.2°, 34.939°±0.2°, 35.947°±0.2°, 36.722°±0.2°, 36.954°±0.2°, 38.075°±0.2°, 39.153°±0.2°, and 39.714°±0.2°, with a radiation source of Cu-Kα.
The pharmaceutical composition according to any one of claim 1-3, comprising:

(a) about 3%to about 30%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof;

(b) about 15%to about 70%by weight of the filler,

(c) about 10%to about 45%by weight of the first polymeric release-controlling excipient,

(d) 0%to about 20%by weight of the second polymeric release-controlling excipient,

(e) 0%to about 40%by weight of the acidulant,

(f) 0%to about 2%by weight of the glidant, and

(g) 0%to about 2%by weight of the lubricant,

based on the total weight of the pharmaceutical composition.
The pharmaceutical composition according to any one of claims 2-4, wherein

the first polymeric release-controlling excipient is HPMC; preferably, the first polymeric release-controlling excipient is HPMC K100 LV; more preferably, the first polymeric release-controlling excipient is HPMC K100 Premium LV DC2; and/or

the second polymeric release-controlling excipient is selected from one or more of HPMC with a viscosity of 3000 to 5600 mPa·s, or HPMC with a viscosity of 40 to 60 mPa·s, and Eudragit with a viscosity of 100 to 200 mPa·s; preferably, the second polymeric release-controlling agent is selected from one or more of HPMC K4M, HPMC E50LV, and Eudragit L100-55; more preferably, the second polymeric release-controlling agent is HPMC K4M.
The pharmaceutical composition according to any one of claims 2-5, wherein

the filler is one or more of microcrystalline cellulose, lactose, dibasic calcium phosphate, and sorbitol; preferably, the filler is microcrystalline cellulose or lactose; more preferably, the filler is lactose;

the acidulant is one or more of tartaric acid, fumaric acid and succinic acid; preferably, the acidulant is tartaric acid, or tartaric acid and fumaric acid; more preferably, the acidulant is tartaric acid and fumaric acid;

the glidant is colloidal silicon dioxide; and/or

the lubricant is magnesium stearate.
The pharmaceutical composition according to any one of claims 2-6, comprising:

about 6%to about 15.2%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof;

about 21.5%to about 64%by weight of the filler;

about 15%to about 40%by weight; preferably, about 25%to about 40%by weight; more preferably, about 30%to about 40%by weight of the first polymeric release-controlling excipient;

about 0%to about 15%by weight of the second polymeric release-controlling excipient;

about 15%to about 35%by weight; preferably, about 15%to about 30%by weight of the acidulant;

about 0%to about 1%by weight; preferably, about 0.5%to about 1%by weight; more preferably, about 1%by weight of the glidant; and/or

about 1%to about 1.5%by weight of the lubricant.
The pharmaceutical composition according to claim 7, comprising:

about 0%to about 30%by weight; preferably, about 15%to about 30%by weight; more preferably, about 20%by weight of the tartaric acid; and/or

about 0%to about 20%by weight; preferably, about 10%to about 20%by weight; more preferably, about 10%by weight of the fumaric acid.
The pharmaceutical composition according to claim 8, comprising about 15%by weight of the tartaric acid, or about 20%by weight of the tartaric acid and about 10%by weight of the fumaric acid; preferably, about 20%by weight of the tartaric acid and about 10%by weight of the fumaric acid.
The pharmaceutical composition according to claim 8 or 9, wherein when the acidulant is the tartaric acid and the fumaric acid, the tartaric acid and the fumaric acid have a mass ratio of about (0.75～2) : 1; preferably about 2: 1.
The pharmaceutical composition according to any one of claims 1-10, wherein the first polymeric release-controlling excipient and the compound of formula (I) , or a pharmaceutically acceptable salt thereof, have a mass ratio of about (1～7) : 1.
The pharmaceutical composition according to claim 11, wherein

when the first polymeric release-controlling excipient and the compound of formula (I) , or a pharmaceutically acceptable salt thereof, have a mass ratio of <1.5: 1, the pharmaceutical composition comprises the second polymeric release-controlling excipient, preferably HPMC K4M, and the second polymeric release-controlling excipient and the compound of formula (I) , or a pharmaceutically acceptable salt thereof, have a mass ratio of about (0.3～1.5) : 1, preferably about (0.3～1) : 1; or

when the first polymeric release-controlling excipient and the compound of formula (I) , or a pharmaceutically acceptable salt thereof, have a mass ratio of about (1.5～7) : 1, the pharmaceutical composition comprises the acidulant, and the acidulant and the compound of formula (I) , or a pharmaceutically acceptable salt thereof, have a mass ratio of about (1～5) : 1.
The pharmaceutical composition according to any one of claims 5-12, wherein:

the microcrystalline cellulose is microcrystalline cellulose PH-102;

the lactose is lactose monohydrate and/or anhydrous lactose; preferably, the lactose is lactose monohydrate; more preferably, the lactose is lactose monohydrate 316;

the HPMC K100 LV is selected from the group consisting of: HPMC K100 Premium LV, HPMC K100 Premium LV CR, and HPMC K100 Premium LV DC2; preferably, the HPMC K100 LV is HPMC K100 Premium LV DC2;

the HPMC K4M is selected from the group consisting of HPMC K4M Premium LV and HPMC K4M Premium CR; preferably, the HPMC K4M is HPMC K4M Premium CR;

the tartaric acid is L-tartaric acid (+) ;

the colloidal silicon dioxide is colloidal silicon dioxide Aerosil 200 Pharma; and/or the magnesium stearate is magnesium stearate LIGAMED MF-2-V.
The pharmaceutical composition according to any one of claims 5-13, comprising:

scheme 1: about 15.2%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 53.8%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 2: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 54%by weight of lactose monohydrate, about 15%by weight of HPMC K100 LV, about 15%by weight of HPMC K4M, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 3: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 54%by weight of lactose monohydrate, about 25%by weight of HPMC K100 LV, about 5%by weight of HPMC K4M, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 4: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 64%by weight of lactose monohydrate, about 20%by weight of HPMC K100 LV, about 15%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 5: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 39%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 15%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 6: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 29%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 10%by weight of Eudragit L100-55, about 15%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 7: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 39%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 8: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 24%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 30%by weight of tartaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 9: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 24%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 15%by weight of HPMC E50LV, about 15%by weight of tartaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 10: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 34%by weight of lactose monohydrate, about 20%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 11: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 24%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 12: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 29%by weight of lactose monohydrate, about 25%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, about 15%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 13: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 24%by weight of lactose monohydrate, about 25%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, about 20%by weight of fumaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 14: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 20%by weight of lactose monohydrate, about 19%by weight of microcrystalline cellulose, about 30%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 15: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 20%by weight of lactose monohydrate, about 19%by weight of dicalcium phosphate, about 30%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 16: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 23.5%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 0.5%by weight of colloidal silicon dioxide, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 17: about 12%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 26%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 0.5%by weight of colloidal silicon dioxide, and about 1.5%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 18: about 12%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 41%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 15%by weight of tartaric acid, about 0.5%by weight of colloidal silicon dioxide, and about 1.5%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 19: about 9%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 23%by weight of lactose monohydrate, about 35%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 1%by weight of colloidal silicon dioxide, and about 2%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 20: about 9%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 23%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 5%by weight of HPMC K4M, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 1%by weight of colloidal silicon dioxide, and about 2%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 21: about 12%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 25%by weight of lactose monohydrate, about 35%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 1%by weight of colloidal silicon dioxide, and about 2%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 22: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 58%by weight of dicalcium phosphate, about 20%by weight of microcrystalline cellulose, about 6%by weight of Carbopol 71GN, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 23: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 54%by weight of lactose monohydrate, about 13.5%by weight of HPMC K100 LV, about 16.5%by weight of HPMC K4M, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 24: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 33.5%by weight of lactose monohydrate, about 20%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 0.5%by weight of colloidal silicon dioxide, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 25: about 15%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 23.5%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, 15%by weight of HPMC E50LV, about 20%by weight of tartaric acid, about 0.5%by weight of colloidal silicon dioxide, and about 1%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition;

scheme 26: about 12%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 25.5%by weight of lactose monohydrate, about 30%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 1%by weight of colloidal silicon dioxide, and about 1.5%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition; or

scheme 27: about 6%by weight of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, about 21.5%by weight of lactose monohydrate, about 40%by weight of HPMC K100 LV, about 20%by weight of tartaric acid, about 10%by weight of fumaric acid, about 1%by weight of colloidal silicon dioxide, and about 1.5%by weight of magnesium stearate; based on the total weight of the pharmaceutical composition.
The pharmaceutical composition according to claim 14, wherein

the compound of formula (I) is in the crystalline form B;

the microcrystalline cellulose is Microcrystalline Cellulose PH-102;

the colloidal silicon dioxide is Colloidal Silicon Dioxide Aerosil 200 Pharma;

the magnesium stearate is Magnesium Stearate Ligamed MF-2-V;

the HPMC K4M is HPMC K4M Premium CR;

the HPMC K100 LV is HPMC K100 Premium LV DC2;

the tartaric acid is L-Tartaric acid (+) /crystal;

the lactose monohydrate is Lactose Monohydrate 316; and/or

the dicalcium phosphate is Dicalcium Phosphate Dihydrate.
The pharmaceutical composition according to claim 14, selected from schemes 1-3, 5-9, 11-18 and 25-27.
The pharmaceutical composition according to any one of claims 1-16, comprising:

about 9.6%by weight of the compound of formula (I) , about 32.2%by weight of Mannitol 100 SD, about 20%by weight of Pregelatinized starch, about 32.2%by weight of Microcrystalline cellulose PH-102, about 3%by weight of Croscarmellose sodium SD-711, about 2%by weight of Magnesium stearate Ligamed MF-2-V, and about 1%by weight of Colloidal silicon dioxide 200 Pharma, based on the total weight of the pharmaceutical composition; the pharmaceutical composition being preferably an immediate release (IR) capsule formulation.
A unit dosage form comprising the pharmaceutical composition according to any one of claims 1-17, wherein the unit dosage form is preferable in the form of a tablet; optionally, the tablet is coated with one or more compendial excipients.
The unit dosage form according to claim 18, comprising about 20 mg to about 80 mg, preferably about 20 mg to about 60 mg, more preferably about 20 mg to about 40 mg, of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition has a mass of about 200 mg to about 400 mg, preferably, about 300 mg to about 400 mg.
A process for preparing the pharmaceutical composition according to any one of claims 1-19, comprising:

blending the compound of formula (I) , or a pharmaceutically acceptable salt thereof, and the filler to obtain a first blend;

blending the first blend with the first polymeric release-controlling excipient, optionally the second polymeric release-controlling excipient, optionally the acidulant, and optionally the glidant to obtain a second blend; and

blending the second blend with the lubricant to obtain the pharmaceutical composition.
The process according to claim 20, further comprising:

compressing the pharmaceutical composition into a tablet; and

optionally, coating the tablet with a non-functional coating made of compendial excipients or a functional coating made of compendial excipients.
A method for treating a JAK1-mediated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition according to any one of claims 1-17 or the unit dosage form of claim 18 or 19.
The method according to claim 22, wherein the disease or disorder is an inflammatory disease, an autoimmune disease, an immune-mediated disease, or cancer.
The method according to claim 22, wherein the JAK1-mediated disease or disorder is selected from asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) , juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease) , endocrinopathies (e.g., type 1 diabetes and Graves’ disease) , neurodegenerative diseases (e.g., multiple sclerosis (MS) ) , autistic spectrum disorder, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, amyotrophic lateral sclerosis (ALS) , Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CID) , vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis) , skin diseases (e.g., acne vulgaris dermatomyositis, pemphigus, systemic lupus erythematosus (SLE) , discoid lupus erthematosus, scleroderma, psoriasis, plaque psoriasis, vasculitics, vitiligo and alopecias) , Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS) , celiac disease, pemphigus, transplant rejection (allograft transplant rejection) , graft-versus-host disease (GVDH) , an inflammatory disease, an autoimmune disease, an immune-mediated disease, cancer, rheumatoid arthritis, ankylosing spondylitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn’s, ulcerative colitis, DES, vitiligo, alopecia areata, and alopecia totalis.
Use of the pharmaceutical composition according to any one of claims 1-17 in the manufacture of a medicament for treating a JAK1-mediated disease or disorder.