Extended-release upadacitinib formulations

Abstract

The present disclosure provides an extended release solid dosage form comprising upadacitinib, or a pharma- ceutically acceptable salt thereof, wherein the solid dosage form has a pH-independent drug release. In particular, the present disclosure describes an extended release solid dosage form comprising upadacitinib, or a pharma- ceutically acceptable salt thereof, at least one pH-dependent polymer, and at least one release-controlling material.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 63 / 131,564, filed December 29, 2020, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Upadacitinib is a Janus kinase (JAK) inhibitor marketed in the United States under the trade name RINVOQ for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have an inadequate response or intolerance to methotrexate. The marketed product is a once-daily extended-release tablet containing tartaric acid as an acidic pH modifier and hydroxypropyl methylcellulose (HPMC) as a release-controlling polymer. In addition to the 15 mg dose of upadacitinib marketed for the treatment of RA, it is also being explored for the treatment of active psoriatic arthritis and active ankylosing spondylitis. In Japan, a lower dose (7.5 mg) is marketed. Higher doses (30 mg and 45 mg) are planned for the treatment of atopic dermatitis and IBD diseases, such as Crohn's disease and ulcerative colitis, respectively. The tablet size for each of these solid dosage forms is close to 500 mg, which can impede swallowing, especially in patients with swallowing difficulties, such as pediatric, young and / or elderly patients. Furthermore, if the tablets are not stored properly (e.g., in low humidity conditions), it has been found that this can adversely affect appearance, dissolution rate and impurity profile. Summary of the Invention [Problem to be solved by the invention]

[0003] Thus, there is a need for improved solid dosage forms containing upadacitinib that retain the desirable characteristics of the marketed product, e.g., a similar dissolution profile, but without the negative characteristics, e.g., swallowability issues and / or storage issues. [Means for solving the problem]

[0004] Provided herein are improved extended release solid dosage forms comprising upadacitinib or a pharma- ceutically acceptable salt thereof.

[0005] In one aspect, the disclosure provides an extended release solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, wherein the solid dosage form provides a pH-independent drug release.

[0006] In one embodiment, the solid dosage form comprises a matrix system. In some such embodiments, the matrix system comprises a pH-dependent polymer. In some such embodiments, the solid dosage form further comprises at least one release-controlling material. In some such embodiments, the solid dosage form comprises less than 10% by weight of a hygroscopic acidic pH adjusting agent.

[0007] In one embodiment, the solid dosage form comprises a release rate modifier, preferably the release rate modifier is not a hygroscopic acidic pH modifier. In some such embodiments, the release rate modifier is an ion exchange resin. In some such embodiments, the release rate modifier is a non-acidic or basic pH modifier, such as sodium carbonate, meglumine, trisodium phosphate dodecahydrate (Na3PO4-12H2O), sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, or calcium phosphate. In some such embodiments, the solid dosage form further comprises an anionic polymer or an anionic polysaccharide, such as hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP), methacrylic acid copolymer (Eudragit L), alginic acid, pectin, hyaluronic acid, or carboxymethylcellulose.

[0008] In one embodiment, the solid dosage form comprises a barrier layer that covers a portion of the release surface of the solid dosage form. In some such embodiments, the barrier layer comprises a polymer, preferably a pH-dependent polymer, that acts as a coating that covers a portion of the release surface of the solid dosage form. In some such embodiments, the pH-dependent barrier layer is applied to a portion of the surface of the dosage form (e.g., tablet) using a solvent-based coating or compression coating process. In some such embodiments, the solid dosage form further comprises a release rate modifier. In some such embodiments, the release rate modifier is an acidic pH modifier, e.g., fumaric acid.

[0009] In one embodiment, the solid dosage form is an osmotic pump drug delivery system. In some such embodiments, the osmotic pump drug delivery system includes a release rate modifier. In some such embodiments, the release rate modifier is an acidic pH modifier, e.g., fumaric acid. In other such embodiments, the osmotic pump drug delivery system does not include a release rate modifier. [Brief description of the drawings]

[0010] [Figure 1A] FIG. 1A shows the effect of tartaric acid present in uncoated (FIG. 1A) and coated (FIG. 1B) upadacitinib-containing tablets. In FIG. 1A, increasing mottle / deliquescence is observed in uncoated tablets containing increasing tartaric acid (TA) content, i.e., 0%, 10%, 20% and 30% TA with a moisture content of 4.2%, upon storage at 30° C. / 53% relative humidity (RH) for 2 months. Without being bound to a particular theory, it is believed that the difference in mottle and dissolution is mainly caused by two factors: (a) solubilization of the water-absorbing organic acid (tartaric acid) in water, which leads to deliquescence and leaching of tartaric acid into the film coat, as shown, for example, in FIG. 1A, and (b) cross-linking of the solubilized tartaric acid with the film coat containing polyvinyl alcohol (PVA), which leads to changes in dissolution, as shown by the change in dissolution of stressed vs. unstressed tablets in FIG. 1B. [Figure 1B]FIG. 1A shows the effect of tartaric acid present in uncoated (FIG. 1A) and coated (FIG. 1B) upadacitinib-containing tablets. In FIG. 1B, a visual comparison of "unstressed" RINVOQ coated 7.5 mg tablets in Table 1 versus "stressed" RINVOQ coated 7.5 mg tablets (exposed to 40° C. / RH 53% for more than 2 months) shows the difference in dissolution in 50 mM sodium phosphate buffer (pH 6.8). Without being bound to a particular theory, it is believed that the mottling and dissolution difference is primarily caused by two factors: (a) solubilization of the water-absorbing organic acid (tartaric acid) in water, which results in deliquescence and leaching of tartaric acid into the film coat, as shown, for example, in FIG. 1A, and (b) cross-linking of the solubilized tartaric acid with the film coat containing polyvinyl alcohol (PVA), which results in changes in dissolution, as shown by the change in dissolution of stressed vs. unstressed tablets in FIG. 1B. [Diagram 2] FIG. 1 shows a reaction scheme for the formation of the non-genotoxic upadacitinib hydroxymethyl impurity (UHM) impurity from reaction of upadacitinib in the presence of acid, water and formaldehyde. [Diagram 3] FIG. 1 compares the dissolution profile of RINVOQ (30 mg) 500 mg tablet at pH 1.1 and pH 6.8 with mini-tablets (200 mg) containing tartaric acid (T1) and without tartaric acid (A1). [Figure 4] FIG. 1 shows the dissolution profile of RINVOQ (30 mg) 500 mg tablet at pH 1.1 and pH 6.8 containing tartaric acid and a release controlling material (HPMC) compared to the dissolution profile of Formulation AS1, a small tablet, which contains an enteric polymer (HPMCAS) and a release controlling material (HPMC). [Diagram 5] FIG. 1 shows the dissolution profile of RINVOQ (30 mg) 500 mg tablet at pH 1.1 and pH 6.8 containing tartaric acid and a release controlling material (HPMC) compared to the dissolution profile of a smaller tablet, Formulation AS2, which contains an enteric polymer (HPMCAS) and a release controlling material (HPMC). [Figure 6] FIG. 1 shows the dissolution profile of RINVOQ (30 mg) 500 mg tablet at pH 1.1 and pH 6.8 containing tartaric acid and a release controlling material (HPMC) compared to the dissolution profile of a smaller tablet, Formulation AS3, which contains an enteric polymer (HPMCAS) and a release controlling material (HPMC). [Figure 7] FIG. 1 shows the dissolution profile of RINVOQ (30 mg) 500 mg tablet at pH 1.1 and pH 6.8 containing tartaric acid and a release controlling material (HPMC) compared to the dissolution profile of a smaller tablet, Formulation AS4, which contains an enteric polymer (HPMCAS) and a release controlling material (HPMC). [Figure 8] FIG. 1 shows the dissolution profile of RINVOQ (30 mg) 500 mg tablet at pH 1.1 and pH 6.8 containing tartaric acid and a release controlling material (HPMC) compared to the dissolution profile of Formulation AS5, a miniature tablet, which contains an enteric polymer (HPMCAS) and a release controlling material (HPMC). [Figure 9] FIG. 1 shows the dissolution profile of a 500 mg tablet of RINVOQ (30 mg) containing tartaric acid and a release controlling material (HPMC) at pH 1.1 and pH 6.8 compared to the dissolution profile of a smaller tablet, Formulation AL1, which contains the anionic polysaccharide alginic acid and a release controlling material (HPMC). [Figure 10] FIG. 1 shows the dissolution profile of a 500 mg tablet of RINVOQ (30 mg) containing tartaric acid and a release controlling material (HPMC) at pH 1.1 and pH 6.8 compared to the dissolution profile of a smaller tablet, Formulation AL2, which contains the anionic polysaccharide alginic acid and a release controlling material (HPMC). [Figure 11]FIG. 1 shows the dissolution profile of a 500 mg tablet of RINVOQ (30 mg) containing tartaric acid and a release controlling material (HPMC) at pH 1.1 and pH 6.8 compared to the dissolution profile of a smaller tablet, Formulation AL3, which contains the anionic polysaccharide alginic acid and a release controlling material (HPMC). [Figure 12] FIG. 1 compares the dissolution profile at pH 1.1 and 6.8 of a RINVOQ (30 mg) 500 mg tablet containing tartaric acid and a release controlling material (HPMC) with the dissolution profile of Formulation T2, a miniature tablet containing an enteric polymer (HPMCAS), a release controlling material (HPMC) and a hygroscopic acidic pH modifier (20% tartaric acid). [Figure 13] FIG. 1 compares the dissolution profile of a 30 mg RINVOQ tablet with the dissolution profile of a 15 mg Formulation E1 tablet in (1) 0.1 N HCl and (2) buffer (pH 6.8). [Figure 14] FIG. 1 compares the dissolution profiles of Formulations E2, E3 and E4 tablets, 30 mg, in (1) 0.1 N HCl and (2) buffer, pH 6.8. [Figure 15] FIG. 1 compares the dissolution profiles of Formulations E4 and E5 tablets, 30 mg, in (1) 0.1 N HCl and (2) buffer, pH 6.8. [Figure 16] FIG. 1 compares the dissolution profiles of Formulations E6 and E7 tablets, 30 mg, in (1) 0.1 N HCl and (2) buffer, pH 6.8. [Figure 17] FIG. 1 compares the dissolution profiles of Formulations E6 and E8 tablets, 30 mg, in (1) 0.1 N HCl and (2) buffer, pH 6.8. [Figure 18] FIG. 1 compares the dissolution profiles of formulations E9, E10 and E11 tablets, 11.52 mg, in (1) 0.1 N HCl and (2) buffer, pH 6.8. [Figure 19] FIG. 1 compares the dissolution profiles of formulations E10 and E12 tablets, 11.52 mg, in (1) 0.1 N HCl and (2) buffer, pH 6.8. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Extended release solid dosage forms comprising upadacitinib ((3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide) or a pharma- ceutically acceptable salt thereof, an acidic pH modifier, such as tartaric acid, and a release controlling polymer, such as hydroxypropylmethylcellulose (HPMC), are described in WO2017 / 066775, including the solid dosage form sold as RINVOQ (upadacitinib). As described and understood in the '775 publication, as the solid dosage form begins to erode following administration and exposure to water in the stomach, the acidic pH modifier and upadacitinib solubilize and form an acidic gel microenvironment with the release-controlling polymer, allowing for the sustained release of upadacitinib from the gel in the solid dosage form at a relatively constant rate despite pH changes in the external macroenvironment. Such a sustained release profile has been found to be particularly advantageous because the pH of the gastrointestinal tract can vary widely from the stomach (e.g., pH about 1.5-3) to the duodenum (e.g., pH about 4-5) to the lower part of the small intestine (e.g., pH about 6.5-7.5).

[0012] It has now become apparent that currently available solid dosage forms have several shortcomings, particularly in relation to storage and handling. For example, with increased storage time without proper moisture protection, tablets become increasingly spotty in appearance (see FIG. 1), the dissolution rate of upadacitinib decreases, and the level of the non-genotoxic upadacitinib hydroxymethyl impurity (UHM impurity) (see FIG. 2) increases. Without being bound to a particular theory, these storage and handling challenges of the commercially available RINVOQ tablets may be due in part to the presence of a relatively high amount (e.g., 20%) of tartaric acid, a hygroscopic organic acid. For example, over time, especially under conditions where a low water environment cannot be maintained, water is absorbed into the tablet (facilitated by the water-loving nature of tartaric acid), making it increasingly solubilized. The tablet spots may be due to either deliquescence and leaching of solubilized tartaric acid through the film coat, and / or cross-linking reaction of solubilized tartaric acid with the film coat containing polyvinyl alcohol (PVA). The decrease in dissolution rate after storage, especially under high temperature and humidity, may be due to the gradual reaction of solubilized tartaric acid with PVA as a crosslinker. The increase in the amount of solubilized tartaric acid may also be due to an increase in the amount of UHM impurity, which may be generated via the tartaric acid-catalyzed reaction of upadacitinib with trace amounts of formaldehyde present in some excipients, e.g., polyethylene glycol (PEG), HPMC, PVA. To maintain low levels of UHM impurities and meet the quality specifications of the commercial product (e.g., about 0.5% w / w or less or about 0.1% to about 0.5% w / w of UHM impurity), it is necessary to maintain low moisture content of the tablets (e.g., about 4% w / w or less or about 1% to about 4% w / w) during the 24-month storage period. Drying the tablets and then storing them under very dry conditions (e.g., using desiccants or sealing in aluminum foil packaging) is not a complete solution.

[0013] Furthermore, it was discovered that the use of tartaric acid as an acidic pH modifier in small tablets to reduce the size of the commercial product and thereby improve swallowability resulted in tablets with incomplete release compared to the commercial product RINVOQ.

[0014] The present disclosure provides novel solid dosage forms comprising upadacitinib or a pharma- ceutically acceptable salt thereof, which provide pH-independent drug release.

[0015] Such solid dosage forms may allow for the reduction or even elimination of certain acidic pH modifiers in the formulation, more particularly hygroscopic organic acids such as tartaric acid. Lowering the level of hygroscopic acids in the formulation can reduce speckle, reduce degradation products (e.g., UHM impurities, etc.), and improve storage stability issues while retaining a release profile similar to the marketed upadacitinib product. Additionally, lower levels of hygroscopic acids in the tablet facilitate manufacturing and require less filler or other excipients to compensate for its content, thus providing a much smaller dosage form size compared to currently marketed RINVOQ tablets.

[0016] Thus, the present disclosure provides solid dosage forms that, for example, improve appearance, dissolution, and / or enhance physical and chemical stability to reduce the formation of degradation products; facilitate swallowability by providing tablets of a size substantially less than 500 mg; provide substantially complete drug release; and / or have a dissolution profile and / or bioavailability that is improved relative to or similar to the dissolution profile of RINVOQ.

[0017] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, at least one pH-dependent polymer, and at least one release-controlling material.

[0018] Without wishing to be bound by a particular theory, it is believed that as a solid dosage form comprising upadacitinib, a pH-dependent polymer and a release-controlling material begins to dissolve and erode following administration and exposure to water in the low pH environment of the stomach, the pH-dependent polymer acts as a diffusion barrier, slowing the drug release rate while the release-controlling material hydrates, forms a gum, gel, and / or swells, thus together controlling the release rate of upadacitinib in the stomach. As the solid dosage form transitions to the more basic pH environment of the intestine, the pH-dependent polymer begins to dissolve, promoting the erosion of the release-controlling material and allowing for the controlled release of upadacitinib in the intestine.

[0019] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof and a release rate modifier, wherein the release rate modifier is not a hygroscopic acidic pH modifier, e.g., tartaric acid. In some such embodiments, the release rate modifier is an ion exchange resin. In some such embodiments, the release rate modifier is a non-acidic or basic pH modifier, and the solid dosage form optionally further comprises an anionic polymer or an anionic polysaccharide.

[0020] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof and a barrier layer covering a portion of the release surface of the solid dosage form.

[0021] In one embodiment, the solid dosage form comprises an osmotic pump drug delivery system.

[0022] In certain embodiments, upadacitinib or a pharma- ceutically acceptable salt thereof, as described herein, is present in the solid dosage form in an amount sufficient to deliver between about 5 and about 50 mg of upadacitinib free base per unit dosage form. In some such embodiments, upadacitinib or a pharma- ceutically acceptable salt thereof is present in the solid dosage form in an amount sufficient to deliver about 7.5 mg of upadacitinib free base per unit dosage form. In some such embodiments, upadacitinib or a pharma- ceutically acceptable salt thereof is present in the solid dosage form in an amount sufficient to deliver about 15 mg of upadacitinib free base per unit dosage form. In some such embodiments, upadacitinib or a pharma- ceutically acceptable salt thereof is present in the solid dosage form in an amount sufficient to deliver about 30 mg of upadacitinib free base per unit dosage form. In some such embodiments, upadacitinib or a pharma- ceutically acceptable salt thereof is present in the solid dosage form in an amount sufficient to deliver about 45 mg of upadacitinib free base per unit dosage form.

[0023] The term "upadacitinib free base" refers to the free base (non-salt, neutral) form of upadacitinib. Examples of solid forms of upadacitinib free base include amorphous upadacitinib free base and crystalline free base of upadacitinib. Specific examples of upadacitinib free base solid forms include, but are not limited to, amorphous upadacitinib free base, upadacitinib free base solvate form A, upadacitinib free base hydrate form B, upadacitinib free base hydrate form C (which is a hemihydrate), and upadacitinib free base anhydrate form D, which are described in International Applications WO2017 / 066775 and WO2018 / 165581, respectively, the contents of each of which are incorporated herein by reference.

[0024] A "pharmaceutical acceptable salt" of upadacitinib refers to a salt suitable for use in pharmaceutical compositions and compatible with the solid dosage forms described herein. Such salts can be obtained, for example, by reaction of upadacitinib free base with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids, such as organic sulfonic acids, organic carboxylic acids, organic phosphoric acids, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g., (+) or (-)-tartaric acid or mixtures thereof), amino acids (e.g., (+) or (-)-amino acids or mixtures thereof), and the like.

[0025] The term "upadacitinib free base equivalent" refers to a dose of neutral upadacitinib free base (active ingredient) that is free of any additional components in solid state form, e.g., free of any solvent or water molecules in the solid state of a solvate or hydrate (including hemihydrate), and free of any pharma- ceutically acceptable salt counter anion in the solid state of a pharma- ceutically acceptable salt. For example, 15.4 mg of crystalline upadacitinib free base hemihydrate (containing ½ water molecule per upadacitinib free base molecule) delivers 15 mg of upadacitinib free base equivalent, and 30.7 mg of crystalline upadacitinib free base hemihydrate (containing ½ water molecule per upadacitinib free base molecule) delivers 30 mg of upadacitinib free base equivalent.

[0026] The term "anhydrous" as applied to a compound refers to the solid state in which the compound does not contain structural water within the crystal lattice.

[0027] As used herein, the term "solid dosage form" is used synonymously with pharmaceutical composition, and both refer to solid formulations suitable for oral administration to humans. Exemplary solid dosage forms include, but are not limited to, tablets (coated or uncoated) and capsules. "Extended release" (also referred to as controlled release or sustained release) solid dosage forms are formulated in a manner that slowly releases the contained drug over an extended period of time, e.g., 0-20 hours, 0-18 hours, 0-16 hours, 0-14 hours, 0-12 hours, 0-10 hours, 0-8 hours, 0-6 hours, or 0-4 hours, with substantially complete release being achieved by about 4 hours to about 20 hours, about 4 hours to about 16 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, about 4 hours to about 6 hours, about 6 hours to about 8 hours, about 6 hours to about 10 hours, or about 6 hours to about 12 hours after ingestion (time 0). For example, comparing an immediate release solid dosage form that allows for release of most or all of the active ingredient in a short period of time (e.g., typically about 60 minutes or less). In certain embodiments, the release is a substantially constant release of upadacitinib from the solid dosage form over an extended period of time. In certain embodiments, the release is a substantially complete release of upadacitinib from the solid dosage form over an extended period of time. In certain embodiments, the solid dosage form is an extended release tablet. As used herein, "substantially constant" refers to a relatively constant rate of dissolution over an extended period of time. Further, as used herein, "substantially complete" refers to at least 95% release of upadacitinib from the solid dosage form over an extended period of time. Complete release refers to 100% release of upadacitinib from the solid dosage form over an extended period of time.

[0028] The term "pH-dependent polymer" refers to a polymer that is insoluble or slightly soluble at low pH (e.g., from about pH 1 to below pH 5) but becomes soluble at higher pH (e.g., pH 5 or higher). In certain embodiments, the pH-dependent polymer may be soluble in a pH range of about pH 5 or higher, e.g., from about pH 5 to about pH 9, from about pH 5 to about pH 8, from about pH 5 to about pH 7, or from about pH 5 to about pH 6, which is generally less acidic than the stomach environment and corresponds approximately to pH values ​​in the small intestine. Exemplary pH-dependent polymers include, but are not limited to, (i) enteric polymers, such as hydroxyalkyl cellulose succinates (e.g., hydroxypropyl methylcellulose acetate succinate (HPMCAS)), hydroxyalkyl methylcellulose phthalates (e.g., hydroxypropyl methylcellulose phthalate (HPMCP)), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), poly(meth)acrylate-methacrylic acid copolymers, such as methyl methacrylate-methacrylic acid copolymers (e.g., Eudragit® L100 or Eudragit® S100), and (ii) anionic polysaccharides, such as alginic acid, pectin, hyaluronic acid, carboxymethylcellulose, polyacrylic acid (PAA), Pluronic-g-poly(acrylic acid) copolymers.

[0029] In certain embodiments, the pH-dependent polymer is selected from the group consisting of enteric polymers, anionic polysaccharides, and combinations thereof. In certain embodiments, the pH-dependent polymer is selected from the group consisting of hydroxyalkyl cellulose acetate succinate, hydroxyalkyl methylcellulose phthalate, cellulose acetate phthalate, poly(meth)acrylate-methacrylic acid copolymer, alginic acid, pectin, hyaluronic acid, carboxymethylcellulose, polyacrylic acid (PAA), Pluronic-g-poly(acrylic acid) copolymer, and combinations thereof. In certain embodiments, the pH-dependent polymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, alginic acid, and combinations thereof. In certain embodiments, the pH-dependent polymer is hydroxypropyl methylcellulose acetate succinate. In one embodiment, the pH-dependent polymer is hydroxypropyl methylcellulose phthalate (HPMCP). In certain embodiments, the pH-dependent polymer is alginic acid.

[0030] In certain embodiments, the pH-dependent polymer is present in the solid dosage form in an amount sufficient to: (a) provide a substantially constant drug release between pH 1.1 and 6.8; (b) provide a substantially complete drug release independent of tablet size, particularly for tablet weights of less than 500 mg, e.g., from about 100 mg to about 400 mg; (c) control the production of upadacitinib degradation products within pharma- ceutically acceptable levels during the shelf life of the solid dosage form; (d) provide a substantially similar dissolution profile compared to the RINVOQ extended release tablets; and / or (e) provide a consistent dissolution profile over the shelf life of the solid dosage form.

[0031] In certain embodiments, the pH-dependent polymer is present in the solid dosage form in an amount of about 10% to about 40% (w / w) by weight of the solid dosage form. In certain embodiments, the pH-dependent polymer is present in the solid dosage form in an amount of about 15% to about 35% (w / w) by weight of the solid dosage form. In certain embodiments, the pH-dependent polymer is present in the solid dosage form in an amount of about 20% to about 30% (w / w) by weight of the solid dosage form. In some such embodiments, the solid dosage form comprises about 20% (w / w) of the pH-dependent polymer. In other such embodiments, the solid dosage form comprises about 25% (w / w) of the pH-dependent polymer. In yet other such embodiments, the solid dosage form comprises about 30% (w / w) of the pH-dependent polymer.

[0032] As used herein, a "release controlling material" is an excipient material whose primary function is to modify the release period of the active pharmaceutical ingredient (upadacitinib) from the dosage form, for example, by swelling in water and / or at low pH and / or forming a viscous substance or gel. In certain embodiments, the release controlling material is a non-polymeric rate controlling material. For example, the non-polymeric rate controlling material can be a release controlling lipid, such as glyceryl dibehenate (e.g., Compritol® 888). In other embodiments, the non-polymeric rate controlling material can include fatty acids, fatty acid esters, mono-, di-, and tri-glycerides of fatty acids, fatty alcohols, waxes of natural and synthetic origin with different melting points, and hydrophobic polymers used in hydrophobic non-swelling matrices. Examples include stearic acid, lauryl, cetyl, or cetostearyl alcohol, glyceryl behenate, carnauba wax, beeswax, candelilla wax, microcrystalline wax, and low molecular weight polyethylene. In other embodiments, the non-polymeric rate controlling material is an insoluble polymer. Insoluble polymers include ammonio methacrylate copolymer fine powder (Eudragit® RL100, PO, RS100, PO), polyvinyl acetate or its mixture with povidone (Kollidon® SR), ethyl cellulose (Ethocel®), cellulose acetate (CA-398-10), cellulose acetate butyrate (CAB-381-20), cellulose acetate propionate (CAP-482-20) and latex dispersions of insoluble polymers (Eudragit® NE-30D, RL-30D, RS-30D, Surelease®). In certain embodiments, the release controlling material is a release controlling polymer. In some such embodiments, the release controlling polymer is a hydrophilic polymer.Exemplary release controlling polymers include, but are not limited to, cellulose derivatives having a viscosity between 100 and 100,000 mmPA-s, hydroxypropyl methylcellulose (e.g., hypromellose 2208 or controlled release grades of hydroxypropyl methylcellulose, including the E, F and K series), copolymers of acrylic acid crosslinked with polyalkenyl polyethers (e.g., Carbopol® polymers), hydroxypropyl cellulose, hydroxyethyl cellulose, nonionic homopolymers of ethylene oxide (e.g., Polyox™), water soluble natural gums of polysaccharides (e.g., xanthan gum, alginic acid, locust bean gum, etc.), crosslinked starch, polyvinyl acetate and polyvinylpyrrolidone.

[0033] In certain embodiments, the at least one controlled release material is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), copolymers of acrylic acid crosslinked with polyalkenyl polyethers, and combinations thereof. In certain embodiments, the at least one controlled release material is selected from the group consisting of hydroxypropyl methylcellulose, hydroxyethyl cellulose, and combinations thereof. In certain embodiments, the at least one controlled release material is hydroxypropyl methylcellulose (HPMC).

[0034] In certain embodiments, the controlled release material is present in the solid dosage form in an amount of about 10% to about 60% (w / w) by weight of the solid dosage form, hi certain embodiments, the controlled release material is present in the solid dosage form in an amount of about 20% to about 50% (w / w) by weight of the solid dosage form.

[0035] In certain embodiments, the solid dosage form comprises a low level (e.g., less than 15%, less than 10%, less than 5%) of a hygroscopic acidic pH adjuster in the composition. In certain embodiments, the hygroscopic acidic pH adjuster is a hygroscopic organic acid. The term "hygroscopic" is used as an adjective to refer to a material, e.g., a pharma- ceutically acceptable excipient, that absorbs or adsorbs a significant amount of moisture from the air or surrounding atmosphere. A "hygroscopic" material is considered "deliquescent" if it absorbs moisture from the air or surrounding atmosphere to such an extent that the material gradually dissolves and / or liquefies. Deliquescence is the most severe case of hygroscopicity. In certain embodiments, a solid dosage form comprising upadacitinib or a pharma-ceutically acceptable salt thereof comprises 15% or less by weight (w / w) of a hygroscopic acidic pH adjuster, 10% or less by weight (w / w) of a hygroscopic acidic pH adjuster, or 5% or less by weight (w / w) of a hygroscopic acidic pH adjuster. In certain embodiments, the solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof comprises 15% or less by weight (w / w) of a hygroscopic organic acid, 10% or less by weight (w / w) of a hygroscopic organic acid, or 5% or less by weight (w / w) of a hygroscopic organic acid. In certain embodiments, the hygroscopic organic acid is selected from the group consisting of tartaric acid, citric acid, and maleic acid. In further particular embodiments, the solid dosage form further comprises a low amount (e.g., less than 15%, less than 10%, less than 5%) of other hygroscopic pharma- ceutically acceptable excipients or materials in the composition. In one embodiment, the solid dosage form comprises at least one release rate modifier. In one embodiment, the at least one release rate modifier is selected from the group consisting of an ion exchange resin, a basic pH modifier, an acidic pH modifier, and combinations thereof. An ion exchange resin suitable for use as a release rate modifier is AmberLite™ IRP 69 or a resin having similar characteristics. In one embodiment, the at least one release rate modifier is AmberLite™ IRP 69. Basic pH modifiers suitable for use as release rate modifiers include, but are not limited to, sodium carbonate (Na2CO3), meglumine, trisodium phosphate dodecahydrate (Na3PO4·12H2O), sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, and calcium phosphate. In one embodiment, the at least one release rate modifier is sodium carbonate.In some such embodiments, the at least one release rate modifier is sodium carbonate monohydrate. Acidic pH modifiers suitable for use as release rate modifiers include, but are not limited to, fumaric acid. In one embodiment, the acidic pH modifier is not a hygroscopic acidic pH modifier. In one embodiment, the at least one release rate modifier is fumaric acid.

[0036] In one embodiment, the release rate modifier is present in the solid dosage form in an amount of about 5% to about 40% (w / w) by weight of the solid dosage form. In some such embodiments, the solid dosage form comprises an ion exchange resin, the ion exchange resin being present in the solid dosage form in an amount of about 20% to about 35% (w / w) by weight of the solid dosage form. In some such embodiments, the solid dosage form comprises about 30% (w / w) of the ion exchange resin. In some such embodiments, the solid dosage form comprises a basic pH adjuster, the basic pH adjuster being present in the solid dosage form in an amount of about 5% to about 25% (w / w) by weight of the solid dosage form. In some such embodiments, the solid dosage form comprises about 10% (w / w) of the basic pH adjuster. In some such embodiments, the solid dosage form comprises an acidic pH adjuster, the acidic pH adjuster being present in the solid dosage form in an amount of about 10% to about 35% (w / w) by weight of the solid dosage form. In some such embodiments, the solid dosage form comprises about 25% by weight (w / w) of the acidic pH adjusting agent, hi other such embodiments, the solid dosage form comprises about 30% by weight (w / w) of the acidic pH adjusting agent.

[0037] In certain embodiments, the solid dosage form comprises additional pharma- ceutically acceptable excipients (e.g., fillers, glidants and / or lubricants), and the total amount of the additional pharma- ceutically acceptable excipients is less than 50% by weight (w / w) of the solid dosage form, less than 45% w / w, less than 40% w / w, less than 35% w / w, less than 30% w / w, less than 25% w / w, less than 20% w / w, less than 15% w / w, less than 10% w / w, or less than 5% w / w.

[0038] In certain embodiments, the solid dosage form includes at least one excipient that functions as a bulking agent. The bulking agent can include, for example, polyols such as dextrose, isomalt, mannitol (e.g., spray-dried mannitol (e.g., Pearlitol® 100SD, Pearlitol® 200SD), sorbitol, lactose, and sucrose; native or pregelatinized starch (e.g., potato starch, corn starch, Starch 1500®, etc.); microcrystalline cellulose (e.g., Avicel® PH 101 or Avicel® PH 102); lactose monohydrate (e.g., Foremost® 316 Fast Flo®); mixtures of isomaltulose derivatives (e.g., galenIQ™ 720); and combinations thereof.

[0039] In certain embodiments, the solid dosage form includes a filler selected from the group consisting of microcrystalline cellulose, lactose, mannitol, and combinations thereof. In some such embodiments, the filler is microcrystalline cellulose. In some such embodiments, the filler is lactose. In some such embodiments, the filler is mannitol.

[0040] In certain embodiments, the one or more fillers are present in the solid dosage form in an amount of about 0.1% to about 50% by weight (w / w).In certain embodiments, the fillers are present in the solid dosage form in an amount of about 15% to about 45% by weight (w / w).

[0041] In certain embodiments, the solid dosage form comprises a first filler and a second filler, and the total amount of the first filler and the second filler present in the solid dosage form is about 15% to about 45% by weight (w / w). In some such embodiments, the first filler is microcrystalline cellulose. In some such embodiments, the second filler is mannitol.

[0042] In certain embodiments, the solid dosage form includes at least one excipient that functions as a glidant. The glidant can include, for example, colloidal silicon dioxide, including highly disperse silica (Aerosil®), or other suitable glidants, such as animal or vegetable fats or waxes.

[0043] In certain embodiments, the glidant is present in the solid dosage form in an amount of about 0.1% to about 5% by weight (w / w). In certain embodiments, the glidant is present in the solid dosage form in an amount of about 0.3% to about 2.5% by weight (w / w). In certain embodiments, the glidant is present in the solid dosage form in an amount of about 0.5% to about 1.5% by weight (w / w). In certain embodiments, the solid dosage form comprises about 0.5% by weight (w / w) of the glidant. In certain embodiments, the solid dosage form comprises about 1% by weight (w / w) of the glidant. In certain embodiments, the glidant is colloidal silicon dioxide.

[0044] In certain embodiments, the solid dosage form includes at least one excipient that functions as a lubricant. The lubricant can include, for example, magnesium and calcium stearate, sodium stearyl fumarate, talc, or any other suitable lubricant.

[0045] In certain embodiments, the lubricant is present in the solid dosage form in an amount of about 0.1% to about 5% by weight (w / w). In certain embodiments, the lubricant is present in the solid dosage form in an amount of about 0.3% to about 2.5% by weight (w / w). In certain embodiments, the lubricant is present in the solid dosage form in an amount of about 0.5% to about 1.5% by weight (w / w). In certain embodiments, the solid dosage form comprises about 1% by weight (w / w) of the lubricant. In certain embodiments, the lubricant is magnesium stearate. In certain embodiments, the lubricant is sodium stearyl fumarate.

[0046] As generally described herein, the present disclosure contemplates a solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one pH-dependent polymer, and at least one release-controlling material.

[0047] In certain embodiments, the pH-dependent polymer is a component of a matrix system comprising upadacitinib or a pharma- ceutically acceptable salt thereof. In some such embodiments, the pH-dependent polymer is present in the solid dosage form matrix but is substantially absent from any coating surrounding the solid dosage form. The pH-dependent polymer (e.g., an enteric polymer) is a component of the solid dosage form matrix, and the enteric polymer may optionally and even be present as part of a film coat to allow for extended sustained release. In certain embodiments, the solid dosage form does not include an enteric coating.

[0048] In certain embodiments, the release-controlling material is a component of a matrix system that contains upadacitinib or a pharma- ceutically acceptable salt thereof.

[0049] In certain embodiments, the pH dependent polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) and the controlled release material is hydroxypropyl methylcellulose (HPMC). In one embodiment, the pH dependent polymer is hydroxypropyl methylcellulose phthalate (HPMCP) and the controlled release material is hydroxypropyl methylcellulose (HPMC). In certain embodiments, the pH dependent polymer is alginic acid and the controlled release material is hydroxypropyl methylcellulose (HPMC). In some such embodiments, the pH dependent polymer and the controlled release material are components of a matrix system containing upadacitinib or a pharma- ceutically acceptable salt thereof.

[0050] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, at least one controlled release material, at least one pH-dependent polymer, and is substantially free of hygroscopic acidic pH adjusting agents in the composition (e.g., greater than about 98%, 99%, 99.9% w / w). In some such embodiments, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, at least one controlled release material, at least one pH-dependent polymer, and is substantially free of hygroscopic organic acids. In one embodiment, the hygroscopic organic acid is selected from the group consisting of tartaric acid, citric acid, and maleic acid.

[0051] In one embodiment, the solid dosage form optionally comprises one or more additional pharma- ceutically acceptable excipients. For example, a solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one controlled release material, and at least a pH-dependent polymer can optionally further comprise one or more additional pharma- ceutically acceptable excipients that function as fillers, binders, glidants, and / or lubricants.

[0052] In certain embodiments, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) as a pH-dependent polymer, hydroxypropyl methylcellulose (HPMC) as a release-controlling material, and optionally at least one filler, at least one glidant, and / or at least one lubricant. In some such embodiments, the at least one filler is microcrystalline cellulose, lactose, mannitol, or a combination thereof. In some such embodiments, the at least one glidant is colloidal silicon dioxide. In some such embodiments, the at least one lubricant is sodium stearyl fumarate or magnesium stearate. In some such embodiments, HPMC-AS and HPMC are components of a matrix system containing upadacitinib or a pharma- ceutically acceptable salt thereof.

[0053] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, hydroxypropylmethylcellulose phthalate (HPMCP) as a pH-dependent polymer, hydroxypropylmethylcellulose (HPMC) as a release-controlling material, and optionally at least one filler, at least one glidant, and / or at least one lubricant. In some such embodiments, the at least one filler is microcrystalline cellulose, lactose, mannitol, or a combination thereof. In some such embodiments, the at least one glidant is colloidal silicon dioxide. In some such embodiments, the at least one lubricant is sodium stearyl fumarate or magnesium stearate. In some such embodiments, HPMCP and HPMC are components of a matrix system containing upadacitinib or a pharma- ceutically acceptable salt thereof.

[0054] In certain embodiments, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, alginic acid as a pH-dependent polymer, hydroxypropylmethylcellulose (HPMC) as a release-controlling material, and optionally at least one filler, at least one glidant, and / or at least one lubricant. In some such embodiments, the at least one filler is microcrystalline cellulose, lactose, mannitol, or a combination thereof. In some such embodiments, the at least one glidant is colloidal silicon dioxide. In some such embodiments, the at least one lubricant is sodium stearyl fumarate or magnesium stearate. In some such embodiments, alginic acid and HPMC are components of a matrix system containing upadacitinib or a pharma- ceutically acceptable salt thereof.

[0055] In certain embodiments, the solid dosage form is a tablet and can be coated with any suitable coating, such as a film coat. A film coat may be used, for example, to contribute to the tablet being easily swallowed. A film coat can also be used to improve taste and provide an elegant appearance. The film coat can include a polyvinyl alcohol-polyethylene glycol graft copolymer, such as Opadry®. The film coat can also include talc as an anti-adherent agent. The film coat can account for less than about 5% by weight of the tablet.

[0056] As generally described herein, the disclosure contemplates a solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof and at least one release rate modifier, such as, for example, an ion exchange resin.

[0057] In one embodiment, the release rate modification agent is an ion exchange resin. In one embodiment, the ion exchange resin is a cation exchange resin. In one embodiment, the solid dosage form comprises an upadacitinib-ion exchange resin complex. In some such embodiments, the upadacitinib-ion exchange resin complex comprises upadacitinib, or a pharma- ceutically acceptable salt thereof, bound to an ion exchange resin.

[0058] Ion exchange resins suitable for use in the solid dosage forms disclosed herein comprise a pharmacologically inert organic and / or inorganic matrix that is water insoluble and preferably contains functional groups that are ionic or can be ionized under appropriate conditions. In some such embodiments, the organic matrix is ​​synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic acid, sulfonated styrene, sulfonated divinylbenzene). In some such embodiments, the inorganic matrix comprises silica gel modified by adding ionic groups.

[0059] Suitable ion exchange resins include, but are not limited to, sulfonated copolymers containing styrene and divinylbenzene. In some such embodiments, the mobile, or exchangeable, cation is sodium. An exemplary cation exchange resin is AmberLite™ IRP 69 (DuPont).

[0060] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof and at least one release rate modifier, and is substantially free of hygroscopic acidic pH modifiers in the composition (e.g., greater than about 98%, 99%, 99.9% w / w). In some such embodiments, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, at least one controlled release material, at least one release rate modifier, and is substantially free of hygroscopic organic acids. In one embodiment, the hygroscopic organic acid is selected from the group consisting of tartaric acid, citric acid, and maleic acid.

[0061] In one embodiment, the solid dosage form optionally comprises one or more additional pharma- ceutically acceptable excipients. For example, a solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof and at least one release rate modifier can optionally further comprise one or more additional pharma- ceutically acceptable excipients that function as fillers, binders, glidants and / or lubricants.

[0062] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, an ion exchange resin as a release rate modifier, and optionally at least one filler, at least one glidant, and / or at least one lubricant. In some such embodiments, the at least one filler is microcrystalline cellulose, lactose, mannitol, or a combination thereof. In some such embodiments, the at least one glidant is colloidal silicon dioxide. In some such embodiments, the at least one lubricant is sodium stearyl fumarate or magnesium stearate.

[0063] As generally described herein, the present disclosure contemplates a solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one release rate modifier, e.g., a basic pH modifier, and optionally, at least one pH-dependent polymer.

[0064] In one embodiment, the release rate modifier is a basic pH modifier. Exemplary basic pH modifiers include, but are not limited to, sodium carbonate, meglumine, trisodium phosphate dodecahydrate (Na3PO4-12H2O), sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, and calcium phosphate. In some such embodiments, the release rate modifier is sodium carbonate monohydrate.

[0065] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, at least one basic pH adjusting agent, and an anionic polymer or anionic polysaccharide, such as hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP), methacrylic acid copolymer (Eudragit L), alginic acid, pectin, hyaluronic acid, or carboxymethylcellulose.

[0066] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, at least one basic pH adjusting agent, and is substantially free of hygroscopic acidic pH adjusting agents in the composition (e.g., greater than about 98%, 99%, 99.9% w / w). In some such embodiments, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, at least one basic pH adjusting agent, at least one pH-dependent polymer, and is substantially free of hygroscopic organic acids. In one embodiment, the hygroscopic organic acid is selected from the group consisting of tartaric acid, citric acid, and maleic acid.

[0067] In one embodiment, the solid dosage form optionally comprises one or more additional pharma- ceutically acceptable excipients. For example, a solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof and at least one basic pH-adjusting agent can optionally further comprise one or more additional pharma- ceutically acceptable excipients functioning as fillers, binders, glidants and / or lubricants. As another example, a solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one basic pH-adjusting agent and at least one pH-dependent polymer can optionally further comprise one or more additional pharma- ceutically acceptable excipients functioning as fillers, binders, glidants and / or lubricants.

[0068] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, a basic pH modifier as a release rate modifier, and optionally at least one filler, at least one glidant, and / or at least one lubricant. In some such embodiments, the at least one filler is microcrystalline cellulose, lactose, mannitol, or a combination thereof. In some such embodiments, the at least one glidant is colloidal silicon dioxide. In some such embodiments, the at least one lubricant is sodium stearyl fumarate or magnesium stearate.

[0069] As generally described herein, the disclosure contemplates a solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof and a barrier layer covering a portion of the release surface (e.g., a partially coated tablet).

[0070] In one embodiment, the solid dosage form comprises a barrier layer that partially covers the release surface of the solid dosage form. In some such embodiments, the barrier layer is applied to a portion of the surface of the solid dosage form. For example, the barrier layer can be applied to one side of the solid dosage form as a coating solution. As another example, the barrier layer can be applied to one side of the solid dosage form by compression coating.

[0071] In one embodiment, the barrier layer comprises a pH-dependent polymer. In some such embodiments, the pH-dependent polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS). For example, a film coating solution containing about 5% by weight of HPMCAS can be applied to a portion (e.g., one side) of the solid dosage form. As another example, a compression coating layer containing about 92% by weight of HPMCAS can be applied to a portion (e.g., one side) of the solid dosage form.

[0072] In one embodiment, the solid dosage form further comprises a release rate modifier. In one embodiment, the release rate modifier is an acidic pH modifier. In some such embodiments, the acidic pH modifier is not a hygroscopic pH modifier. In some such embodiments, the release rate modifier is fumaric acid.

[0073] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, at least one non-hygroscopic acidic pH adjusting agent, a barrier layer comprising a pH-dependent polymer, and the composition is substantially free (e.g., greater than about 98%, 99%, 99.9% w / w) of hygroscopic acidic pH adjusting agent. In one embodiment, the hygroscopic organic acid is selected from the group consisting of tartaric acid, citric acid, and maleic acid.

[0074] In one embodiment, the solid dosage form optionally comprises one or more additional pharma- ceutically acceptable excipients. For example, a solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one acidic pH modifier, and a barrier layer comprising a pH-dependent polymer can optionally further comprise one or more additional pharma- ceutically acceptable excipients that function as fillers, binders, glidants, and / or lubricants.

[0075] In one embodiment, the solid dosage form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, an acidic pH modifier as a release rate modifier, a barrier layer comprising a pH-dependent polymer, and optionally at least one filler, at least one glidant, and / or at least one lubricant. In some such embodiments, the at least one filler is microcrystalline cellulose, lactose, mannitol, or a combination thereof. In some such embodiments, the at least one glidant is colloidal silicon dioxide. In some such embodiments, the at least one lubricant is sodium stearyl fumarate or magnesium stearate.

[0076] As generally described herein, the disclosure contemplates solid dosage forms comprising upadacitinib or a pharma- ceutically acceptable salt thereof, the solid dosage forms including osmotic pump systems.

[0077] In an exemplary osmotic pump system, a core is surrounded by a semipermeable membrane having at least one drug delivery orifice. The core contains an active agent and, optionally, at least one osmogent. The semipermeable membrane is permeable to aqueous liquids, e.g., water or biological fluids, but is impermeable to the active agent. When the system is exposed to an aqueous environment, water penetrates through the semipermeable membrane into the core. Osmotic pressure increases within the dosage form, and the active agent (i.e., upadacitinib or a pharma- ceutically acceptable salt thereof) is released through the drug delivery orifice.

[0078] Suitable osmogents include, but are not limited to, water soluble salts of inorganic acids (e.g., magnesium sulfate, magnesium chloride, sodium chloride, sodium sulfate, potassium chloride, sodium bicarbonate, sodium phosphate), osmotic polymers (e.g., polyoxyethylene, polyvinylpyrrolidone, polyacrylic acid, hydroxypropylmethylcellulose, hydroxyethylcellulose (HEC)), carbohydrates (e.g., raffinose, sucrose, glucose, sorbitol, xylitol), and combinations thereof. An exemplary osmogent is sorbitol, which is available as NEOSORB® P 60 W (Roquette).

[0079] Suitable materials for forming the semipermeable membrane include, but are not limited to, cellulose esters, cellulose monoesters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester ethers, and combinations thereof. In one embodiment, the semipermeable membrane comprises cellulose acetate (CA). An exemplary semipermeable membrane system is Opadry® CA Fully Formulated Osmotic Coating System (Colorcon).

[0080] In one embodiment, the core comprises two or more compartments or layers. For example, the core may comprise a bilayer tablet having an active drug-containing layer and a push layer. In one embodiment, the core comprises a separation layer between the active drug-containing layer and the push layer (e.g., a trilayer tablet). In some such embodiments, the push layer comprises an osmotic polymer that promotes swelling of the push layer after exposure to an aqueous environment. Thus, when the osmotic pump system is exposed to an aqueous environment, e.g., the gastrointestinal tract, the push layer swells and pushes the active drug through the drug delivery orifice.

[0081] In one embodiment, the osmopolymer is a swellable hydrophilic polymer. Suitable osmopolymers include, but are not limited to, polyoxyethylene, polyvinylpyrrolidone, polyacrylic acid, hydroxypropylmethylcellulose, hydroxyethylcellulose (HEC), and combinations thereof. An exemplary osmopolymer is Natrosol™ 250HX (Ashland).

[0082] Osmotic pumps are well known in the art and described in the literature, for example, U.S. Patent Nos. 4,088,864, 4,200,098, and 5,573,776, which describe osmotic pumps and methods for their manufacture and are incorporated herein by reference.

[0083] In general, an osmotic pump system can be formed by compressing a tablet of an osmotically active drug (or an osmotically inactive drug in combination with an osmogen) and then coating the tablet with a semipermeable membrane. One or more drug delivery orifices can be drilled into the semipermeable membrane. In one embodiment, the size of the drug delivery orifice is about 0.1 mm to about 4.0 mm, e.g., about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2.0 mm, or about 2.5 mm. Alternatively, the orifice through the wall can be formed in situ by incorporating a leachable pore-forming material in the semipermeable membrane. During operation, an aqueous-based external fluid is imbibed through the semipermeable membrane and contacts at least one active agent to form an active agent solution or suspension. The active agent solution or suspension is then "pumped" through the orifice as fresh fluid is imbibed through the semipermeable membrane.

[0084] In one embodiment, the solid dosage form comprises (i) a core comprising an active drug-containing layer comprising upadacitinib or a pharma- ceutically acceptable salt thereof and an osmogent and a push layer comprising an osmopolymer, e.g., hydroxyethylcellulose (HEC), and (ii) a semipermeable membrane surrounding the core. In some embodiments, the semipermeable membrane contains at least one drug delivery orifice. In some embodiments, the at least one drug delivery orifice is mechanically or laser drilled into the semipermeable membrane.

[0085] In one embodiment, the solid dosage form optionally comprises one or more additional pharma- ceutically acceptable excipients. For example, the core of the solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, an osmogent and an osmopolymer can optionally further comprise one or more additional pharma- ceutically acceptable excipients that function as fillers, binders, glidants and / or lubricants. In some such embodiments, the solid dosage form optionally further comprises a lubricant, such as magnesium stearate.

[0086] In at least one embodiment, the present disclosure is directed to providing upadacitinib or a pharma- ceutically acceptable salt thereof in a single stable oral dosage form. The solid dosage forms disclosed herein are intended for pharmaceutical use in human subjects. Thus, they should be of a size and weight appropriate for oral administration to humans (e.g., they should have a total weight of less than 500 mg, preferably about 100 mg to about 400 mg, more preferably about 150 mg to about 300 mg). In certain embodiments, the solid dosage forms have a total weight of less than 400 mg, less than 350 mg, less than 300 mg, less than 250 mg, less than 200 mg, or less than 150 mg. In some such embodiments, the solid dosage form has a total weight of about 150 mg to about 300 mg, for example, a total weight of about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg. To facilitate ingestion of such dosage forms by mammals, the dosage form may be formed into a suitable shape, for example, a circular, oval, elongated, or the like.

[0087] In at least one embodiment, the solid dosage form is stable, for example, during storage, distribution, and the shelf life of the product (eg, up to 2 years at room temperature / ambient conditions).

[0088] In certain embodiments, the dissolution profile of a stable solid dosage form does not change materially over time.

[0089] In certain embodiments, a stable solid dosage form exhibits less degradation of upadacitinib or a pharma- ceutically acceptable salt thereof and / or produces fewer decomposition products over time compared to RINVOQ.

[0090] The solid dosage form can be evaluated for stability after storage for at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In particular, storage stability can be evaluated at time intervals of 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, 36 months, and / or 48 months. Storage conditions can be long-term, intermediate, or accelerated conditions. In particular, the storage conditions may be, for example, 25°C±2°C / relative humidity (RH) 40%±RH5%, 25°C±2°C / RH 60%±RH5%, 30°C±2°C / RH 35%±RH5%, 30°C±2°C / RH 65%±RH5%, 30°C±2°C / RH 75%±RH5%, 40°C±2°C / RH 25%±RH5%, 40°C±2°C / RH 50%±RH5%, 40°C±2°C / RH 75% ±RH5%, 50°C±2°C / RH75%±RH5%, 60°C±2°C / RH5%±RH5%, 60°C±2°C / RH40%±RH5%, 60°C±2°C / RH50%±RH5%, 70°C±2°C / RH5%±RH5%, 70°C±2°C / RH75%±RH5%, 80°C±2°C / RH40%±RH5% and / or 80°C±2°C / RH75%±RH5%.

[0091] In certain embodiments, storage of the solid dosage form is at 25° C.±2° C. and 60%±5% relative humidity for between about 3 months and about 48 months, between about 6 months and about 36 months, or between about 12 months and about 24 months.

[0092] In certain embodiments, a stable solid dosage form contains no more than pharma- ceutically acceptable levels of upadacitinib degradation products, hi some such embodiments, the excipients contained in the solid dosage form control the formation of upadacitinib degradation products within pharma-ceutically acceptable levels during the shelf life of the solid dosage form.

[0093] One exemplary degradation product of upadacitinib is (3S,4R)-3-ethyl-4-(3-(hydroxymethyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib hydroxymethyl impurity; "UHM impurity"), shown in Figure 2. In certain embodiments, the solid dosage form contains 1% or less of the UHM impurity. In certain embodiments, the solid dosage form contains 0.5% or less of the UHM impurity. In certain embodiments, the solid dosage form contains 0.2% or less of the UHM impurity.

[0094] In certain embodiments, the solid dosage form contains no more than 0.2% UHM impurities at the time of product release and no more than 0.5% UHM impurities at the end of the dosage form's shelf life.

[0095] In certain embodiments, the UHM impurity is present in an amount of less than 0.5% by weight in the solid dosage form after storage under long-term, intermediate, or accelerated conditions for at least 1 month, at least 2 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some such embodiments, the storage conditions may be 25° C.±2° C. / RH60%±RH5%. In some such embodiments, the storage conditions may be 40° C.±2° C. / RH75%±RH5%.

[0096] In certain embodiments, the solid dosage form contains a moisture content of 2.5% or less upon release and 4.0% or less at the end of the shelf life of the dosage form.

[0097] In certain embodiments, the solid dosage form exhibits a dissolution profile after storage that is substantially similar to the initial dissolution profile of the solid dosage form (eg, before storage).

[0098] The assay of solid dosage forms, more particularly tablets, and the determination of degradation products can be carried out using methods and equipment well known to those skilled in the art, for example, HPLC with UV detection. In a particular embodiment, dissolution is evaluated using USP Apparatus I (basket) at 37°C ± 0.5°C with a rotation speed of 150 rpm in 900 mL of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride. In a particular embodiment, dissolution is evaluated using USP Apparatus I (basket) at 37°C ± 0.5°C with a rotation speed of 150 rpm in 900 mL of 0.025 M sodium phosphate buffer (pH 6.8). In a particular embodiment, dissolution is evaluated using USP Apparatus I (basket) at 37°C ± 0.5°C with a rotation speed of 150 rpm in 900 mL of 0.050 M sodium phosphate buffer (pH 6.8). In a particular embodiment, dissolution is assessed in 900 mL of 0.1 N HCl (pH 1.1) utilizing USP Apparatus I (basket) at a rotation speed of 150 rpm at 37° C.±0.5° C.

[0099] In certain embodiments, the solid dosage form exhibits drug release for at least 4 hours, at least 6 hours, or at least 8 hours when added to test medium in a standard USP basket apparatus with a rotation speed of 150 rpm, in certain embodiments, the release is approximately linear, exhibiting a substantially similar amount of drug released per unit time over at least 4 hours, at least 6 hours, or at least 8 hours.

[0100] In certain embodiments, the solid dosage form, when added to test medium in a standard USP basket apparatus with a rotation speed of 150 rpm, dissolves 85% or less of the solid dosage form of upadacitinib after about 1 hour; dissolves 85% or less of the solid dosage form of upadacitinib after about 2 hours; dissolves about 10% to about 65% of the solid dosage form of upadacitinib after about 2 hours; dissolves about 35% to about 90% of the solid dosage form of upadacitinib after about 4 hours; and / or dissolves about 70% to 100% of the solid form of upadacitinib after about 10 hours. In some such embodiments, the test medium comprises 900 mL of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37° C.±0.5° C. In some such embodiments, the test medium comprises 900 mL of 0.025 M sodium phosphate buffer, pH 6.8, at 37° C.±0.5° C. In some such embodiments, the test medium comprises 900 mL of 0.050 M sodium phosphate buffer, pH 6.8, at 37° C.±0.5° C. In some embodiments, the test medium comprises 900 mL of 0.1 N HCl, pH 1.1, at 37° C.±0.5° C.

[0101] In certain embodiments, when the solid dosage form is added to test medium containing 900 mL of sodium phosphate buffer (pH 6.8) at 37°C ± 0.5°C in a standard USP basket apparatus with a rotation speed of 150 rpm, about 80% or less of the solid dosage form of upadacitinib dissolves after about 4 hours, and / or about 80% to 100% of the solid dosage form of upadacitinib dissolves after about 10 hours.

[0102] Dissolution profiles can be compared using model-independent or model-dependent methods. A model-independent approach and comparison criteria using similarity factors are described in SUPAC-MR, Modified Release Solid dosage forms (September 1997).

[0103] Dissolution profiles can be compared using the following equation, which defines the similarity factor (f2):

[0104]

number

[0105] f between 50 and 100 2 A value of 0.1 suggests that the two dissolution profiles are similar, and in certain embodiments, the average difference at any dissolution sampling time point should be no more than about 25%, alternatively no more than about 15%, alternatively no more than about 10% between the post-storage dissolution profile and the initial dissolution profile.

[0106] In certain embodiments, the solid dosage form exhibits a dissolution profile comparable to that of the marketed (or to be marketed) RINVOQ extended release tablet formulation, as described herein. Thus, in certain embodiments, the average difference at any dissolution sampling time point should be about 25% or less, alternatively about 15% or less, or alternatively about 10% or less, between the solid dosage form dissolution profile and the RINVOQ dissolution profile.

[0107] In certain embodiments, the percentage of compound released from the solid dosage form at any dissolution sampling time point is within about 25%, alternatively within about 15%, alternatively within about 10% of the percentage of compound released from the commercially available (or to be commercially available) RINVOQ extended release tablet. For example, a reference sample (e.g., RINVOQ) in which about 91% and about 100% of the equivalent upadacitinib free base is released after 6 hours and 8 hours, respectively, in 900 ml of 0.1 N HCl (pH 1.1) at 37° C. with a rotation speed of 150 rpm using USP I methodology, a test sample (e.g., a solid dosage form described herein) in which about 68% to about 100% and / or about 75% to about 100% of the equivalent upadacitinib free base is released after 6 hours and 8 hours, respectively, would be considered to have a similar dissolution profile under the same conditions. In some such embodiments, a reference sample (e.g., RINVOQ) in which about 75%, about 91%, and about 100% of upadacitinib free base is released after 4 hours, 6 hours, and 8 hours, respectively, using USP I methods in 900 ml of 0.1 N HCl (pH 1.1) at 37°C and a rotation speed of 150 rpm, and a test sample (e.g., a solid dosage form described herein) in which about 56% to about 94%, about 68% to about 100%, and / or about 75% to about 100% of upadacitinib free base is released after 4 hours, 6 hours, and 8 hours, respectively, are considered to have similar dissolution profiles under the same conditions.

[0108] As another example, a reference sample (e.g., RINVOQ) in which about 68% and about 79% of upadacitinib free base is released after 6 hours and 8 hours, respectively, in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37°C using USP I methods at a rotation speed of 150 rpm, and a test sample (e.g., a solid dosage form described herein) in which about 51% to about 85% and / or about 59% to about 99% of upadacitinib free base is released after 6 hours and 8 hours, respectively, would be considered to have a similar dissolution profile if, under the same conditions, about 51% to about 85% and / or about 59% to about 99% of upadacitinib free base is released after 6 hours and 8 hours, respectively. In some such embodiments, a reference sample (e.g., RINVOQ) in which about 54%, about 68%, and about 79% of upadacitinib free base is released after 4, 6, and 8 hours, respectively, in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37°C using USP I methods at a rotation speed of 150 rpm, and a test sample (e.g., a solid dosage form described herein) in which about 41% to about 68%, about 51% to about 85%, and / or about 59% to about 99% of upadacitinib free base is released after 4, 6, and 8 hours, respectively, would be considered to have a similar dissolution profile if, under the same conditions, about 41% to about 68%, about 51% to about 85%, and / or about 59% to about 99% of upadacitinib free base is released after 4, 6, and 8 hours, respectively. In some such embodiments, a reference sample (e.g., RINVOQ) in which about 54%, about 68%, about 79% and about 86% of upadacitinib free base is released after 4, 6, 8 and 10 hours, respectively, in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37°C using USP I methods at a rotation speed of 150 rpm, and a test sample (e.g., a solid dosage form described herein) in which about 41% to about 68%, about 51% to about 85%, about 59% to about 99%, and / or about 65% to about 100% of upadacitinib free base is released after 4, 6, 8 and 10 hours, respectively, are considered to have similar dissolution profiles under the same conditions.In some such embodiments, a reference sample (e.g., RINVOQ) and a test sample (e.g., a solid dosage form described herein) that releases about 54%, about 68%, about 79%, about 86%, and about 90% of upadacitinib free base after 4, 6, 8, 10, and 12 hours, respectively, using USP I methodology in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37° C. and a rotation speed of 150 rpm, are considered to have similar dissolution profiles if, under the same conditions, about 41% to about 68%, about 51% to about 85%, about 59% to about 99%, about 65% to about 100%, and / or about 68% to about 100% of upadacitinib free base is released after 4, 6, 8, 10, and 12 hours, respectively. A reference sample (e.g., RINVOQ) in which about 54%, about 68%, about 79%, about 86%, about 90%, and about 95% of upadacitinib free base was released after 4, 6, 8, 10, 12, and 16 hours, respectively, in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37°C with a rotation speed of 150 rpm using Method I. A test sample (e.g., a solid dosage form described herein) is considered to have a similar dissolution profile if, under the same conditions, about 41% to about 68%, about 51% to about 85%, about 59% to about 99%, about 65% to about 100%, about 68% to about 100%, and / or about 71% to about 100% of the upadacitinib free base is released after 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 16 hours, respectively.In some such embodiments, the reference sample (e.g., RINVOQ), test sample (e.g., 100 mL) and / or test sample (e.g., 120 mL) were assayed using USP I methodology to release about 54%, about 68%, about 79%, about 86%, about 90%, about 95%, and about 97% of upadacitinib free base after 4, 6, 8, 10, 12, 16, and 18 hours, respectively, in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37° C. and a rotation speed of 150 rpm. For example, a solid dosage form described herein is considered to have a similar dissolution profile if, under the same conditions, about 41% to about 68%, about 51% to about 85%, about 59% to about 99%, about 65% to about 100%, about 68% to about 100%, about 71% to about 100%, and / or about 73% to about 100% of upadacitinib free base is released after 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, and 18 hours, respectively. Using Method I, about 54%, about 68%, about 79%, about 86%, about 90%, about 95%, about 97% and about 98% of upadacitinib free base was released after 4, 6, 8, 10, 12, 16, 18 and 20 hours, respectively, in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37°C with a rotation speed of 150 rpm for the reference sample (e.g., RINVOQ), the test sample (e.g., a solid dosage form described herein) is considered to have a similar dissolution profile if, under the same conditions, about 41% to about 68%, about 51% to about 85%, about 59% to about 99%, about 65% to about 100%, about 68% to about 100%, about 71% to about 100%, about 73% to about 100%, and / or about 74% to about 100% of the upadacitinib free base is released after 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 18 hours, and 20 hours, respectively.

[0109] As yet another example, a reference sample (e.g., RINVOQ) in which about 80% and about 89% of upadacitinib free base is released after 6 hours and 8 hours, respectively, in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) at 37°C using USP I methods at a rotation speed of 150 rpm, and a test sample (e.g., a solid dosage form described herein) in which about 60% to about 100% and / or about 67% to about 100% of upadacitinib free base is released after 6 hours and 8 hours, respectively, would be considered to have a similar dissolution profile if, under the same conditions, about 60% to about 100% and / or about 67% to about 100% of upadacitinib free base is released after 6 hours and 8 hours, respectively. In some such embodiments, a reference sample (e.g., RINVOQ) and a test sample (e.g., a solid dosage form described herein) in which about 65%, about 80%, and about 89% of upadacitinib free base is released after 4, 6, and 8 hours, respectively, using USP I methods at a rotation speed of 150 rpm and 37°C, are considered to have similar dissolution profiles if, under the same conditions, about 49% to about 81%, about 60% to about 100%, and / or about 67% to about 100% of upadacitinib free base is released after 4, 6, and 8 hours, respectively. In some such embodiments, a reference sample (e.g., RINVOQ) and a test sample (e.g., a solid dosage form described herein) that releases about 65%, about 80%, about 89% and about 94% of upadacitinib free base after 4, 6, 8 and 10 hours, respectively, using USP I methods at a rotation speed of 150 rpm and 37°C, are considered to have similar dissolution profiles if, under the same conditions, about 49% to about 81%, about 60% to about 100%, about 67% to about 100%, and / or about 71% to about 100% of upadacitinib free base is released after 4, 6, 8 and 10 hours, respectively.In some such embodiments, a reference sample (e.g., RINVOQ), a test sample (e.g., a solid dosage form described herein) that releases about 65%, about 80%, about 89%, about 94%, and about 97% of upadacitinib free base after 4, 6, 8, 10, and 12 hours, respectively, using USP I methodology at a rotation speed of 150 rpm in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) at 37° C. is considered to have a similar dissolution profile if, under the same conditions, about 49% to about 81%, about 60% to about 100%, about 67% to about 100%, about 71% to about 100%, and / or about 73% to about 100% of upadacitinib free base is released after 4, 6, 8, 10, and 12 hours, respectively. A reference sample (e.g., RINVOQ) in which about 65%, about 80%, about 89%, about 94%, about 97% and about 100% of upadacitinib free base is released after 4, 6, 8, 10, 12 and 16 hours, respectively, in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) at 37°C using Method I at a rotation speed of 150 rpm, and a test sample (e.g., a solid dosage form described herein) in which about 49% to about 81%, about 60% to about 100%, about 67% to about 100%, about 71% to about 100%, about 73% to about 100% and / or about 75% to about 100% of upadacitinib free base is released after 4, 6, 8, 10, 12 and 16 hours, respectively, are considered to have similar dissolution profiles under the same conditions.

[0110] As yet another example, a reference sample (e.g., RINVOQ) in which about 77% and about 87% of upadacitinib free base is released after 6 hours and 8 hours, respectively, in 900 ml of 0.050 M sodium phosphate buffer (pH 6.8) at 37°C using USP I methods at a rotation speed of 150 rpm, and a test sample (e.g., a solid dosage form described herein) in which about 58% to about 96% and / or about 65% to about 100% of upadacitinib free base is released after 6 hours and 8 hours, respectively, would be considered to have a similar dissolution profile if, under the same conditions, about 58% to about 96% and / or about 65% to about 100% of upadacitinib free base is released after 6 hours and 8 hours, respectively. In some such embodiments, a reference sample (e.g., RINVOQ) and a test sample (e.g., a solid dosage form described herein) that releases about 63%, about 77%, and about 87% of upadacitinib free base after 4, 6, and 8 hours, respectively, using USP I methods at a rotation speed of 150 rpm in 900 ml of 0.050 M sodium phosphate buffer (pH 6.8) at 37°C would be considered to have similar dissolution profiles if, under the same conditions, about 47% to about 79%, about 58% to about 96%, and / or about 65% to about 100% of upadacitinib free base is released after 4, 6, and 8 hours, respectively. In some such embodiments, a reference sample (e.g., RINVOQ) and a test sample (e.g., a solid dosage form described herein) that releases about 63%, about 77%, about 87% and about 93% of upadacitinib free base after 4, 6, 8 and 10 hours, respectively, using USP I methods at a rotation speed of 150 rpm in 900 ml of 0.050 M sodium phosphate buffer (pH 6.8) at 37°C would be considered to have similar dissolution profiles if, under the same conditions, about 47% to about 79%, about 58% to about 96%, about 65% to about 100%, and / or about 70% to about 100% of upadacitinib free base is released after 4, 6, 8 and 10 hours, respectively.In some such embodiments, a reference sample (e.g., RINVOQ) and a test sample (e.g., a solid dosage form described herein) that releases about 63%, about 77%, about 87%, about 93%, and about 96% of upadacitinib free base after 4, 6, 8, 10, and 12 hours, respectively, using USP I methodology at a rotation speed of 150 rpm and 37° C., are considered to have similar dissolution profiles if, under the same conditions, about 47% to about 79%, about 58% to about 96%, about 65% to about 100%, about 70% to about 100%, and / or about 72% to about 100% of upadacitinib free base is released after 4, 6, 8, 10, and 12 hours, respectively. A reference sample (e.g., RINVOQ) in which about 63%, about 77%, about 87%, about 93%, about 96% and about 100% of upadacitinib free base is released after 4, 6, 8, 10, 12 and 16 hours, respectively, in 900 ml of 0.050 M sodium phosphate buffer (pH 6.8) at 37°C with a rotation speed of 150 rpm, and a test sample (e.g., a solid dosage form described herein) in which about 47% to about 79%, about 58% to about 96%, about 65% to about 100%, about 70% to about 100%, about 72% to about 100% and / or about 75% to about 100% of upadacitinib free base is released after 4, 6, 8, 10, 12 and 16 hours, respectively, using Method I are considered to have similar dissolution profiles if, under the same conditions, about 47% to about 79%, about 58% to about 96%, about 65% to about 100%, about 70% to about 100%, about 72% to about 100% and / or about 75% to about 100% of upadacitinib free base is released after 4, 6, 8, 10, 12 and 16 hours, respectively.

[0111] In certain embodiments, the solid dosage forms described herein have a dissolution profile similar to that of the commercially available (or to be commercially available) RINVOQ extended release tablets at 6 hours. In certain embodiments, the solid dosage forms described herein have a dissolution profile similar to that of the commercially available (or to be commercially available) RINVOQ extended release tablets at 8 hours. In certain embodiments, the solid dosage forms described herein have a dissolution profile similar to that of the commercially available (or to be commercially available) RINVOQ extended release tablets at 6 hours and 8 hours. In certain embodiments, the solid dosage forms described herein have a dissolution profile similar to that of the commercially available (or to be commercially available) RINVOQ extended release tablets at 4 hours, 6 hours, and 8 hours. In certain embodiments, the solid dosage forms described herein have a dissolution profile similar to that of the commercially available (or to be commercially available) RINVOQ extended release tablets at 6 hours, 8 hours, and 10 hours. In certain embodiments, the solid dosage forms described herein have a dissolution profile similar to that of the commercially available (or to be commercially available) RINVOQ extended release tablets at 6 hours, 8 hours, 10 hours, and 12 hours. In certain embodiments, the solid dosage forms described herein have a dissolution profile similar to that of the commercially available (or to be commercially available) RINVOQ extended release tablets at 6 hours, 8 hours, 10 hours, 12 hours, and 16 hours. In certain embodiments, the solid dosage forms described herein have a dissolution profile similar to that of the commercially available (or to be commercially available) RINVOQ extended release tablets at 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 16 hours.

[0112] Solid dosage forms can be prepared by any suitable method. Upadacitinib or a pharma- ceutically acceptable salt thereof can be blended with one or more excipients using methods such as direct compression, dry granulation compression, wet granulation compression, or melt granulation.

[0113] In certain embodiments, the solid dosage form comprises a tablet. In some such embodiments, the tablet is a compressed tablet and / or a milled tablet. For example, in some embodiments, the tablet is formed by blending the components (e.g., including the active ingredient and at least one pharma- ceutically acceptable carrier). The components can then be directly compressed, or one or more components can be granulated prior to compression. In one embodiment, milling is performed using a mill equipped with any suitable size screen (e.g., about 600 to about 1400 μm, or about 610 μm or about 1397 μm screen size). Compression can be performed in a tablet press, such as a steel die between two movable punches.

[0114] In other embodiments, the compressed and / or crushed tablets are formulated using a wet granular compression process. The use of a wet granular compression process helps reduce and / or eliminate sticking that can occur when tablets are formulated using compression that does not involve wet granular compression (e.g., direct compression).

[0115] Exemplary Embodiments Embodiment 1. In one embodiment, the extended release solid form comprises upadacitinib or a pharma- ceutically acceptable salt thereof, at least one pH-dependent polymer, and at least one release-controlling material. Embodiment 2. The sustained release solid dosage form of embodiment 1, wherein the dosage form comprises less than 10% by weight of a hygroscopic acidic pH adjusting agent. Embodiment 3. The extended release solid dosage form of embodiment 1, wherein the dosage form is substantially free of hygroscopic acidic pH adjusting agents. Embodiment 4. The sustained release solid dosage form of embodiment 2 or 3, wherein the hygroscopic acidic pH adjusting agent is an organic acid. Embodiment 5. The sustained release solid dosage form of embodiment 4, wherein the hygroscopic organic acid is selected from the group consisting of tartaric acid, citric acid and maleic acid. Embodiment 6. The extended release solid dosage form of any one of embodiments 1-5, wherein the solid dosage form further comprises one or more additional excipients selected from the group consisting of fillers, binders, glidants, lubricants, film coats, and combinations thereof; and wherein the one or more additional excipients are present in an amount of less than 50% w / w of the solid dosage form. Embodiment 7. The extended release solid dosage form of any one of embodiments 1 to 6, wherein the at least one pH-dependent polymer and the at least one release controlling material comprise a matrix system containing upadacitinib or a pharma- ceutically acceptable salt thereof. Embodiment 8. The sustained release solid dosage form of any one of embodiments 1-7, wherein the dosage form does not include an enteric film coat. Embodiment 9. The sustained release solid dosage form of any one of embodiments 1 to 8, wherein the at least one pH-dependent polymer is an enteric polymer or an anionic polysaccharide. Embodiment 10. The sustained release solid dosage form of any one of embodiments 1 to 9, wherein the at least one pH-dependent polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or alginic acid. Embodiment 11. The sustained release solid dosage form of any one of embodiments 1 to 10, wherein the at least one pH-dependent polymer is present in an amount of about 20% to about 40% w / w of the solid dosage form, and the at least one release-controlling material is present in an amount of about 30% to about 60% w / w of the solid dosage form. Embodiment 12. The sustained release solid dosage form of any one of embodiments 1 to 11, wherein at least one release-controlling material is a release-controlling polymer. Embodiment 13. The sustained release solid dosage form of any one of embodiments 1 to 11, wherein the at least one release controlling polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, hydroxyethyl cellulose, copolymers of acrylic acid crosslinked with polyalkenyl polyethers (Carbopol), non-ionic homopolymers of ethylene oxide (Polyox), water soluble natural gums of polysaccharides, crosslinked starch, polyvinyl acetate, polyvinylpyrrolidone, and combinations thereof. Embodiment 14. The extended release solid dosage form of any one of embodiments 1 to 13, wherein upadacitinib or a pharma- ceutically acceptable salt thereof is present in the solid dosage form in an amount sufficient to deliver 5 mg to 50 mg of upadacitinib free base per dosage unit. Embodiment 15. The extended release solid dosage form of any one of embodiments 1-14, wherein after storage, the solid dosage form continues to retain (a) pharma- ceutically acceptable levels of degradation products of upadacitinib, and / or (b) a dissolution profile after storage substantially similar to its initial dissolution profile. Embodiment 16. The extended release solid dosage form of embodiment 15, wherein the solid dosage form contains 0.5% w / w or less of degradation products of upadacitinib during the shelf-life of the solid dosage form, and wherein the shelf-life of the solid dosage form is about 6 months, about 12 months, about 18 months, about 24 months, about 30 months, or about 36 months. Embodiment 17. The extended release solid dosage form of embodiment 15 or embodiment 16, wherein the upadacitinib degradation product is (3S,4R)-3-ethyl-4-(3-(hydroxymethyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. Embodiment 18. The sustained release solid dosage form of any one of embodiments 15 to 17, wherein storage of the solid dosage form is at 25°C ± 2°C and 60% ± 5% relative humidity for between about 3 months and about 48 months, between about 6 months and about 36 months, or between about 12 months and about 24 months. Embodiment 19. The initial dissolution profile is about 85% or less of the upadacitinib released from the solid dosage form in about 1 hour or about 2 hours, about 10% to about 65% of the upadacitinib released from the solid dosage form in about 2 hours, about 35% to about 90% of the upadacitinib released from the solid dosage form in about 4 hours, and / or about 70% to 100% of the upadacitinib released from the solid dosage form in about 10 hours; The sustained release solid dosage form according to any one of embodiments 15 to 18, wherein the initial dissolution profile is measured in 900 mL of (1) 0.025 M sodium phosphate buffer (pH 6.8), (2) 0.025 M phosphate buffer (pH 6.8), (3) 0.050 M phosphate buffer (pH 6.8), or (4) 0.1 N HCl (pH 1.1), containing 2.75% sodium chloride, at a rotation speed of 150 rpm and at 37°C ± 2°C using a USP I apparatus. Embodiment 20. The sustained release solid dosage form of any one of embodiments 15 to 19, wherein at least one pH-dependent polymer is an enteric polymer or an anionic polysaccharide. Embodiment 21. The sustained release solid dosage form of any one of embodiments 15 to 20, wherein the at least one pH-dependent polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or alginic acid. Embodiment 22. The sustained release solid dosage form of any one of embodiments 1 to 21, having a total weight of less than 400 mg. Embodiment 23. The sustained release solid dosage form of embodiment 22, having a total weight of between about 100 mg and about 300 mg. Embodiment 24. In another embodiment, there is provided a stable solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one pH-dependent polymer, and at least one release-controlling material; having less than 0.2% w / w of upadacitinib degradation products in the solid dosage form at an initial time point and having less than 0.5% w / w of upadacitinib degradation products in the solid dosage form at a time point after storage; the initial and post-storage time points being at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months apart, during which the composition is at 25°C±2°C and 60%±5% relative humidity; An upadacitinib degradation product is (3S,4R)-3-ethyl-4-(3-(hydroxymethyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. Embodiment 25. The stable solid dosage form of embodiment 24, wherein the at least one pH-dependent polymer is an enteric polymer or an anionic polysaccharide. Embodiment 26. The stable solid dosage form of embodiment 25, wherein the at least one pH-dependent polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or alginic acid. Embodiment 27. The stable solid dosage form of any one of embodiments 24-26, wherein about 68% to about 100% of the upadacitinib is released from the solid dosage form in about 6 hours in 900 ml of 0.1 N HCl (pH 1.1) at 37°C and a rotation speed of 150 rpm using the USP I method, and / or about 75% to about 100% of the upadacitinib is released from the solid dosage form in about 8 hours in 900 ml of 0.1 N HCl (pH 1.1) at 37°C and a rotation speed of 150 rpm using the USP I method. Embodiment 28. The stable solid dosage form of embodiment 27, wherein about 56% to about 94% of the upadacitinib is released from the solid dosage form in about 4 hours in 900 ml of 0.1 N HCl (pH 1.1) at 37°C and a rotation speed of 150 rpm using the USP I method. Embodiment 29. The stable solid dosage form of any one of embodiments 24-26, wherein about 51% to about 85% of upadacitinib is released from the solid dosage form in about 6 hours using the USP I method in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37°C and a rotation speed of 150 rpm, and / or about 59% to about 99% of upadacitinib is released from the solid dosage form in about 8 hours using the USP I method in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37°C and a rotation speed of 150 rpm. Embodiment 30. The stable solid dosage form of embodiment 29, wherein about 41% to about 68% of the upadacitinib is released from the solid dosage form in about 4 hours in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37°C and a rotation speed of 150 rpm using USP I method. Embodiment 31. The stable solid dosage form of any one of embodiments 24-26, wherein about 60% to about 100% of upadacitinib is released from the solid dosage form in about 6 hours using the USP I method in 900 ml of 0.025 M sodium phosphate buffer, pH 6.8 at 37°C and a rotation speed of 150 rpm, and / or about 67% to about 100% of upadacitinib is released from the solid dosage form in about 8 hours using the USP I method in 900 ml of 0.025 M sodium phosphate buffer, pH 6.8 at 37°C and a rotation speed of 150 rpm. Embodiment 32. The stable solid dosage form of embodiment 31, wherein about 49% to about 81% of the upadacitinib is released from the solid dosage form in about 4 hours in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) at 37°C and a rotation speed of 150 rpm using USP I method. Embodiment 33. The stable solid dosage form of any one of embodiments 24-26, wherein about 58% to about 96% of upadacitinib is released from the solid dosage form in about 6 hours using the USP I method in 900 ml of 0.050 M sodium phosphate buffer, pH 6.8 at 37°C and a rotation speed of 150 rpm, and / or about 65% to about 100% of upadacitinib is released from the solid dosage form in about 8 hours using the USP I method in 900 ml of 0.050 M sodium phosphate buffer, pH 6.8 at 37°C and a rotation speed of 150 rpm. Embodiment 34. The stable solid dosage form of embodiment 33, wherein about 47% to about 79% of the upadacitinib is released from the solid dosage form in about 4 hours in 900 ml of 0.050 M sodium phosphate buffer (pH 6.8) at 37°C and a rotation speed of 150 rpm using the USP I method. Embodiment 35. A sustained release solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one pH-dependent polymer, and at least one release-controlling material; and further comprising a basic pH modulating agent. Embodiment 36. The extended release solid dosage form of embodiment 35, wherein the basic pH adjusting agent is sodium carbonate, meglumine, or trisodium phosphate dodecahydrate. Embodiment 37. The sustained release solid dosage form of embodiment 35 or 36, wherein the basic pH adjusting agent is present in the solid dosage form in an amount of about 5% to about 25% by weight (w / w) of the solid dosage form. Embodiment 38. The extended release solid dosage form of any one of embodiments 35 to 37, wherein the at least one pH-dependent polymer and the at least one release controlling material comprise a matrix system containing upadacitinib or a pharma- ceutically acceptable salt thereof. Embodiment 39. The sustained release solid dosage form of any one of embodiments 35 to 38, wherein the dosage form does not include an enteric film coat. Embodiment 40. The sustained release solid dosage form of any one of embodiments 35 to 39, wherein at least one pH-dependent polymer is an enteric polymer or an anionic polysaccharide. Embodiment 41. The sustained release solid dosage form of any one of embodiments 35 to 40, wherein the at least one pH-dependent polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or alginic acid. Embodiment 42. The sustained release solid dosage form according to any one of embodiments 35 to 41, wherein the at least one pH-dependent polymer is present in an amount of about 20% to about 40% w / w of the solid dosage form, and the at least one release-controlling material is present in an amount of about 30% to about 60% w / w of the solid dosage form. Embodiment 43. A sustained release solid dosage form comprising upadacitinib, or a pharma- ceutically acceptable salt thereof, at least one release rate modifier and at least one release controlling material, wherein (a) the at least one release rate modifier comprises an ion exchange resin, or (b) the at least one release rate modifier comprises a basic pH modifier, and the sustained release solid dosage form further comprises an anionic polymer. Embodiment 44. The sustained release solid dosage form of embodiment 43, wherein at least one release rate modification agent is an ion exchange resin. Embodiment 45. The sustained release solid dosage form of embodiment 44, wherein the ion exchange resin comprises a sulfonated copolymer comprising styrene and divinylbenzene. Embodiment 46. The extended release solid dosage form of embodiment 44, wherein the upadacitinib or a pharma- ceutically acceptable salt thereof and the ion exchange resin form an upadacitinib-ion exchange resin complex, wherein the upadacitinib-ion exchange resin complex comprises upadacitinib or a pharma- ceutically acceptable salt thereof bound to an ion exchange resin. Embodiment 47. The sustained release solid dosage form of embodiment 43, wherein the at least one release rate modifier is a basic pH modifier, and the sustained release solid dosage form further comprises an anionic polymer. Embodiment 48. The sustained release solid dosage form of embodiment 47, wherein the basic pH adjusting agent is present in an amount of about 5% to about 20% w / w. Embodiment 49. The sustained release solid dosage form of embodiment 47 or 48, wherein the basic pH adjusting agent is sodium carbonate, meglumine, or trisodium phosphate dodecahydrate. Embodiment 50. A sustained release solid dosage form comprising: a core comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one release rate modifier, and at least one release controlling material; and a barrier layer partially covering the core. Embodiment 51. The sustained release solid dosage form of embodiment 50, wherein at least one release rate modifier is an acidic pH modifier. Embodiment 52. The sustained release solid dosage form of embodiment 50 or 51, wherein the barrier layer comprises a pH-dependent polymer. Embodiment 53. The sustained release solid dosage form of embodiment 52, wherein the pH-dependent polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS). Embodiment 54. The sustained release solid dosage form of any one of embodiments 35 to 53, wherein the dosage form comprises less than 10% by weight of a hygroscopic acidic pH adjusting agent. Embodiment 55. The extended release solid dosage form of any one of embodiments 35-53, wherein the dosage form is substantially free of hygroscopic acidic pH adjusting agents. Embodiment 56. The sustained release solid dosage form of embodiment 54 or 55, wherein the hygroscopic acidic pH adjuster is an organic acid. Embodiment 57. The sustained release solid dosage form of embodiment 54 or 55, wherein the hygroscopic organic acid is selected from the group consisting of tartaric acid, citric acid and maleic acid. Embodiment 58. The sustained release solid dosage form according to any one of embodiments 35 to 57, wherein at least one release-controlling material is a release-controlling polymer. Embodiment 59. The sustained release solid dosage form of any one of embodiments 35 to 58, wherein the at least one release controlling polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, hydroxyethyl cellulose, copolymers of acrylic acid crosslinked with polyalkenyl polyethers (Carbopol), non-ionic homopolymers of ethylene oxide (Polyox), water-soluble natural gums of polysaccharides, crosslinked starch, polyvinyl acetate, polyvinylpyrrolidone, and combinations thereof. Embodiment 60. The extended release solid dosage form of any one of embodiments 35-59, wherein the solid dosage form further comprises one or more additional excipients selected from the group consisting of fillers, binders, glidants, lubricants, film coats, and combinations thereof; and wherein the one or more additional excipients are present in an amount of less than 50% w / w of the solid dosage form. Embodiment 61. A sustained release solid dosage form comprising a core comprising upadacitinib, or a pharma- ceutically acceptable salt thereof; a semipermeable membrane covering the core, the semipermeable membrane being permeable to aqueous fluids and substantially impermeable to upadacitinib; and at least one drug delivery orifice providing a passageway by which upadacitinib or a pharma- ceutically acceptable salt thereof may be released from the core to an environment external to the sustained release solid dosage form. Embodiment 62. The sustained release solid dosage form of embodiment 61, wherein the core further comprises an osmogent. Embodiment 63. The sustained release solid dosage form of embodiment 62, wherein the osmagenta comprises a water-soluble salt of an inorganic acid, an osmotic polymer, a carbohydrate, or a combination thereof. Embodiment 64. A sustained release solid dosage form according to any one of embodiments 61 to 63, wherein the core is monolayer or multilayer. Embodiment 65. The sustained release solid dosage form of any one of embodiments 61 to 63, wherein the core comprises a push layer. Embodiment 66. The sustained release solid dosage form of embodiment 65, wherein the push layer comprises an osmotic polymer, preferably hydroxyethyl cellulose (HEC). Embodiment 67. The sustained release solid dosage form of any one of embodiments 61 to 66, wherein the semipermeable membrane comprises cellulose acetate (CA). EXAMPLES

[0116] Example The solid dosage forms described herein will be better understood with reference to the following examples, which are included as illustrative, but not limiting, of the scope of the disclosure.

[0117] Example 1: RINVOQ formulations containing acidic pH modifiers and release-controlling polymers The marketed (or to be marketed) formulations for RINVOQ extended release tablets are shown in Table 1. Upadacitinib tablets containing 0%, 10%, 20% and 30% tartaric acid (TA) are shown in Table 2.

[0118] [Table 1]

[0119] [Table 2]

[0120] The RINVOQ tablets in Table 1 have several disadvantages.

[0121] Figures 1A and 1B show mottle of uncoated upadacitinib-containing tablets containing 0%, 10%, 20% and 30% tartaric acid RINVOQ coated tablets 7.5 mg. See Tables 1 and 2. In Figure 1A, increasing mottle / deliquescence is observed in uncoated tablets containing increasing amounts of tartaric acid (TA), i.e., 0%, 10%, 20% and 30% TA with a moisture content of 4.2%, when stored for 2 months at 30°C / 53% relative humidity (RH). In Figure 1B, visual comparison of "unstressed" RINVOQ coated tablets 7.5 mg vs. "stressed" RINVOQ coated tablets 7.5 mg in Table 1 (over 2 months at 40°C / 53% RH) shows differences in dissolution in 50 mM phosphate buffer (pH 6.8). Without being bound to any particular theory, it is believed that the mottling and dissolution differences are primarily caused by two factors: (a) solubilization of water-absorbing organic acids in water, resulting in deliquescence and leaching of tartaric acid from the film coat, as shown in Figure 1 A, and (b) cross-linking of the solubilized tartaric acid by the film coat containing polyvinyl alcohol (PVA), as shown by the change in dissolution in Figure 1 B. The stressed RINVOQ tablets showed slower dissolution because at least a portion of the film coat was not completely dissolved due to cross-linking.

[0122] Another disadvantage of the RINVOQ tablets in Table 1 is the increasing impurity levels of the non-genotoxic upadacitinib hydroxymethyl impurity (UHM impurity) over time. As shown in Figure 2, the UHM impurity is formed by reaction of water, upadacitinib, tartaric acid and trace amounts of formaldehyde present in excipients such as polyethylene glycol, HPMC, PVA, etc. The UHM impurity can be characterized using standard techniques such as NMR, HPLC and / or KF titration.

[0123] UHM impurities were observed at levels of up to 0.19% (practical limit of quantitation in the study was 0.10%) in the RINVOQ film-coated tablets in Table 1 stored at 40°C / 75% RH for 6 months. At 12 months, 30°C / 75% RH, UHM impurities were observed at levels of up to 0.07% (practical limit of quantitation in the study was 0.03%). Stability data showed that UHM impurities increased over time, especially for tablets containing 7.5 mg upadacitinib free base equivalent and / or for tablets stored in blister packs.

[0124] Table 3 summarizes stability data obtained from the solid dosage form described herein (AS2 formulation blend; see Example 3), as well as historical stability data obtained from formulation blends containing RINVOQ extended release tablets and RINVOQ tablet excipients. "Formulation blend" refers to a blend of loose powders prior to compression into tablets.

[0125] [Table 3]

[0126] Example 2: Mini-tablets with and without TA and comparison with RINVOQ In this example, we sought to address another disadvantage of the RINVOQ tablets in Table 1, namely, the relatively large tablet size (approximately 500 mg).

[0127] Formulation A1 (no tartaric acid): 3.84 g upadacitinib, 12.5 g HPMC K4M, 16.4 g Avicel PH102, 1.50 g hydroxypropylcellulose, 0.25 g colloidal silicon dioxide, and 15.00 g mannitol were sieved through a 30 mesh screen into a 250 mL bottle and blended in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with 0.50 g sodium stearyl fumarate, then blended in a Turbula blender for approximately 2 minutes and compressed into 200 mg oval tablets on a Carver press.

[0128] Formulation T1 (with tartaric acid): Upadacitinib 7.68 g, HPMC K4M 12.5 g, Avicel PH102 2.57 g, hydroxypropylcellulose 1.50 g, colloidal silicon dioxide 0.25 g, mannitol 15.00 g, and tartaric acid 10.00 g were sieved through a 30 mesh screen, added to a 250 mL bottle, and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with sodium stearyl fumarate 0.50 g, then mixed in a Turbula blender for approximately 2 minutes, and compressed into 200 mg oval tablets in a Carver press. The formulation for the small tablets is shown in Table 4.

[0129] [Table 4]

[0130] The in vitro dissolution rates of formulations A1 (without TA) and T1 (with TA) were determined using USP I methodology at 37° C. with a rotation speed of 150 rpm using (1) 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride, and (2) 900 ml of 0.1 N HCl (pH 1.1), and compared to the RINVOQ 30 mg formulation in Table 1. The test results are shown in Tables 5A, 5B, and FIG. 3.

[0131] [Table 5]

[0132] [Table 6]

[0133] This data demonstrates the difficulty in designing a small tablet of upadacitinib with a similar sustained release profile as the RINVOQ formulation, but with less (or no) tartaric acid. For example, small tablet formulation T1 (200 mg) containing 20% ​​tartaric acid showed a release profile comparable to RINVOQ (30 mg) at pH 1.1 and pH 6.8, but virtually no complete release was observed at pH 6.8. Small tablet formulation A1 (200 mg), with a 15 mg dose but no tartaric acid present, demonstrated a release profile comparable to RINVOQ (30 mg) at pH 1.1, but a different release profile at pH 6.8. Small tablets have an increased surface-to-mass ratio, which may be one of the factors that impair the release rate at different pHs. However, in general, formulations containing tartaric acid have proven less effective in small tablets; see, for example, Example 4, which explores the use of tartaric acid in a pH-dependent polymer / controlled release material formulation. Thus, when reducing tablet size, an alternative approach was required to achieve similar drug release to commercially available RINVOQ.

[0134] [Example 3] Enteric polymer as pH-dependent polymer To explore alternative approaches to improve the smaller tablet size and physical and chemical stability of RINVOQ tablets, a compact extended-release formulation of upadacitinib containing an enteric polymer and a release-controlling material was prepared using direct compression.

[0135] Formulation AS1: Upadacitinib 3.69 g, HPMC K4M 12.00 g, HPMCAS 9.00 g, Avicel PH102 5.01 g were sieved through a 35 mesh screen into a 125 mL bottle and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with magnesium stearate and compressed into 250 mg oval tablets on a Carver press.

[0136] Formulation AS2: Upadacitinib 3.84 g, HPMC K4M 20.0 g, Avicel PH102 8.91 g, hydroxypropylcellulose 1.50 g, colloidal silicon dioxide 0.25 g, and HPMCAS 15.00 g were sieved through a 30 mesh screen and added to a 250 mL bottle and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with sodium stearyl fumarate 0.50 g, then mixed in a Turbula blender for approximately 2 minutes and compressed into 200 mg oval tablets on a Carver press.

[0137] Formulation AS3: Upadacitinib 10.24 g, HPMC K4M 22.5 g, Avicel PH102 0.013 g, hydroxypropylcellulose 1.5 g, colloidal silicon dioxide 0.25 g, and HPMCAS 15.0 g were sieved through a 30 mesh screen and added to a 250 mL bottle and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with sodium stearyl fumarate 0.50 g, then mixed in a Turbula blender for approximately 2 minutes and compressed into 150 mg oval tablets on a Carver press.

[0138] Formulation AS4: Upadacitinib 7.68 g, HPMC K4M 12.5 g, Avicel PH102 12.57 g, mannitol 5 g, hydroxypropylcellulose 1.5 g, colloidal silicon dioxide 0.25 g, and HPMCAS 10 g were sieved through a 30 mesh screen into a 250 mL bottle and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with sodium stearyl fumarate 0.50 g, then mixed in a Turbula blender for approximately 2 minutes and compressed into 200 mg oval tablets on a Carver press.

[0139] Formulation AS5: Upadacitinib 7.68 g, HPMC K4M 10 g, Avicel PH102 7.57 g, mannitol 12.5 g, hydroxypropylcellulose 1.5 g, colloidal silicon dioxide 0.25 g, and HPMCAS 10 g were sieved through a 30 mesh screen into a 250 mL bottle and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with sodium stearyl fumarate 0.50 g, then mixed in a Turbula blender for approximately 2 minutes and compressed into 200 mg oval tablets on a Carver press.

[0140] Formulation AS6: Upadacitinib 1.54 g, HPMC K4M 12 g, HPMCAS 9 g, and lactose 7.16 g were sieved through a 35 mesh screen into a 125 mL bottle and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with magnesium stearate and compressed into 300 mg oval tablets on a Carver press. Formulation AS7: Upadacitinib 7.68 g, HPMC K4M 20.0 g, Avicel PH102 4.07 g, hydroxypropylcellulose 2.50 g, colloidal silicon dioxide 0.25 g, and HPMCAS 15.00 g were sieved through a 30 mesh screen and added to a 250 mL bottle and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with magnesium stearate 0.50 g, then mixed in a Turbula blender for approximately 2 minutes and compressed into 200 mg oval tablets on a Carver press.

[0141] The formulations of AS1-AS7 are shown in Tables 6A and 6B.

[0142] [Table 7]

[0143] [Table 8]

[0144] The in vitro dissolution rates of formulations AS1, AS2, and AS3 were determined using USP I method in (1) 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride, and (2) 900 ml of 0.1 N HCl (pH 1.1) at 37° C. with a rotation speed of 150 rpm. The in vitro dissolution rates of formulations AS4 and AS5 were determined using USP I method in (1) 0.025 M sodium phosphate buffer (pH 6.8), and (2) 900 ml of 0.1 N HCl (pH 1.1) at 37° C. with a rotation speed of 150 rpm. The RINVOQ (30 mg) formulations of the dissolution profiles in Table 1 are shown in Table 4. The test results shown in Tables 7A and 7B and Figures 4 to 8 indicate that the small tablet formulations AS1 to AS5 each provided an extended drug release comparable to that of the large RINVOQ (30 mg) formulation, with sustained release and substantially steady release observed for up to 10 to 12 hours at pH 1.1 and 6.8 for AS1 to AS3, and sustained release and substantially steady release observed for up to 8 to 10 hours for AS4 and AS5. The rate differences at pH 1.1 and pH 6.8 for formulations AS1-AS5 versus RINVOQ were small despite significant solubility differences of upadacitinib at pH 1.1 and pH 6.8 (i.e., the solubility of upadacitinib ranges from 38.4±1.5 mg / mL in 0.1 N HCl medium (pH 1.0) at 37°C to 0.194±0.001 mg / mL in 50 mM sodium phosphate buffer (pH 7.02) at 37°C).

[0145] [Table 9]

[0146] [Table 10]

[0147] [Example 4] Anionic polysaccharides as pH-dependent polymers To explore alternative approaches to improve the smaller tablet size and physical and chemical stability of RINVOQ tablets, a compact extended-release formulation of upadacitinib containing an anionic polysaccharide (alginic acid) and a release-controlling material was also prepared by direct compression.

[0148] Formulation AL1: Upadacitinib 4.6 g, HPMC K4M 7.5 g, alginic acid 9 g, Avicel PH102 4.5 g, mannitol 3 g, hydroxypropylcellulose 0.9 g, colloidal silicon dioxide 0.15 g were sieved through a 35 mesh screen into a 125 mL bottle and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with sodium stearyl fumarate, then mixed in a Turbula blender for approximately 2 minutes and compressed into 200 mg oval tablets on a Carver press.

[0149] Formulation AL2: Upadacitinib 2.3 g, HPMC K4M 9.00 g, alginic acid 7.5 g, Avicel PH102 6.8 g, mannitol 3 g, hydroxypropylcellulose 0.9 g, colloidal silicon dioxide 0.15 g were sieved through a 35 mesh screen into a 125 mL bottle and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with sodium stearyl fumarate, then mixed in a Turbula blender for approximately 2 minutes and compressed into 200 mg oval tablets on a Carver press.

[0150] Formulation AL3: Upadacitinib 2.3 g, HPMC K4M 10.5 g, alginic acid 7.5 g, Avicel PH102 5.3 g, mannitol 3 g, hydroxypropylcellulose 0.9 g, and colloidal silicon dioxide 0.15 g were sieved through a 35 mesh screen into a 125 mL bottle and mixed in a Turbula blender for approximately 5 minutes. This powder blend was then mixed with sodium stearyl fumarate, then mixed in a Turbula blender for approximately 2 minutes and compressed into 200 mg oval tablets on a Carver press.

[0151] Formulation tablets containing alginic acid (AL) are shown in Table 8.

[0152] [Table 11]

[0153] The in vitro dissolution rates of formulations AL1, AL2 and AL3 were determined using USP I method in 900 ml of (1) 0.050 M sodium phosphate buffer (pH 6.8) and (2) 0.1 N HCl (pH 1.1) at 37° C. with a rotation speed of 150 rpm. The test results, shown in Tables 9A and 9B and Figures 9-11, show comparable drug release profiles to the small tablets AS1-AS5 and the large RINVOQ (30 mg) formulation, with sustained release for up to 8-12 hours, and substantially steady release was observed at pH 1.1 and 6.8. As noted for AS1-AS5, despite significant differences in upadacitinib solubility at pH 1.1 and pH 6.8, the rate differences at pH 1.1 and 6.8 for formulations AL1-AL3 versus RINVOQ were small (i.e., upadacitinib solubility ranges from 38.4±1.5 mg / mL in 0.1 N HCl medium (pH 1.0) at 37°C to 0.194±0.001 mg / mL in 50 mM phosphate buffer (pH 7.02) at 37°C).

[0154] [Table 12]

[0155] [Table 13]

[0156] Example 5: Effect of hygroscopic acidic pH adjusters in pH-dependent polymer / controlled release polymer formulations As shown in Figure 12, formulation T2 containing 20% ​​tartaric acid demonstrates a dissolution profile at pH 1.1 similar to the dissolution profile of the RINVOQ 30 mg tablet in Table 1, while at pH 6.8 it demonstrates a different dissolution profile. This data suggests that the inclusion of a higher amount (e.g., 20% or more) of a hygroscopic acidic pH modifier, such as tartaric acid, may result in a different dissolution profile than RINVOQ.

[0157] [Table 14]

[0158] The in vitro dissolution rate of formulation T2 was determined using USP I method in 900 ml of (1) 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% NaCl and (2) 0.1 N HCl (pH 1.1) containing 2.75% NaCl at 37° C. with a rotation speed of 150 rpm. The results of the performed test for T2 are shown in Table 11. Also shown in FIG. 12 is the dissolution profile compared to the dissolution profile of RINVOQ (30 mg) tablets in Table 1 under the same dissolution conditions.

[0159] [Table 15]

[0160] Example 6: Incorporation of ion exchange resin (IER) as a release rate modifier ER hydrophilic matrix tablets containing 15 mg or 30 mg of upadacitinib were prepared by direct compression using hydroxypropyl methylcellulose as the rate controlling polymer. The compositions of the tablet formulations and the reference product (RINVOQ Tablet 30 mg) are shown in Table 1.

[0161] Formulation E1 was prepared as follows:The following ingredients were sieved through a 30 mesh screen: upadacitinib 0.614g, HPMC K750 2.0g, HPC EXF 0.3g, Amberlite IRP 69 3.0g, Avicel 102 2.01g, Pearlitol 100 SD 1.926g, and colloidal silicon dioxide 0.05g, and mixed in a Turbula blender (49 rpm) for approximately 5 minutes. This powder blend was then mixed with magnesium stearate 0.1g for an additional 2 minutes before being compressed into 250 mg oval tablets in a Carver press. Each tablet contains 15 mg of upadacitinib (anhydrous form). The compositions of Formulation E1 and the reference product are shown in Table 12.

[0162] The in vitro dissolution rate of Formulation E1 was determined using USP 1 method in (1) 50 mM phosphate buffer (pH 6.8) and (2) 900 ml of 0.1 N HCl containing 50 mM sodium chloride at 37° C. with a basket rotation speed of 100 rpm. The in vitro dissolution rate of RINVOQ tablets 30 mg was determined using USP 1 method in (1) 50 mM phosphate buffer (pH 6.8) and (2) 900 ml of 0.1 N HCl at 37° C. with a basket rotation speed of 100 rpm. The dissolution test results shown in Table 13 and FIG. 13 indicate that a similar sustained release was obtained when compared to the reference product (30 mg RINVOQ). Further advantages include near zero order release, smaller and easier to swallow tablets, and minimal difference in release rate between 0.1 N HCl and pH 6.8, despite significant differences in the solubility of the drug substance at pH 1.2 and pH 6.8, i.e., pH-independent release.

[0163] [Table 16]

[0164] [Table 17]

[0165] Example 7: Incorporation of anionic polymers and basic pH adjusters In this study, three formulations were prepared containing HPMCP (HP-55) or Na2CO3 or a combination of HPMC HP-55 and Na2CO3 as the release rate modifier. All three formulations of ER hydrophilic matrix tablets were prepared using direct compression. The materials shown in Table 14 were weighed and sieved through a 30 mesh screen before blending. The drug and all excipients except magnesium stearate (MgSt) were first blended in a Turbula blender at 49 rpm for 5 minutes, followed by addition of MgSt and blending for an additional 2 minutes. The final blend was compressed into 200 mg tablets at approximately 3000 lbs in a Carver press using an oval tooling. Each tablet contains 30 mg of upadacitinib (anhydrous form).

[0166] [Table 18]

[0167] In vitro dissolution rates were determined using USP 1 method in (1) 0.1N HCl, (2) 50 mM phosphate buffer (pH 6.8) 900 ml at 37°C with basket rotation speed of 100 rpm. At least three tablets were used under each test condition. The dissolution results shown in Table 15 and Figure 14 indicate that extended drug release was obtained for all three formulations. pH-dependent dissolution was obtained for formulations E2 and E3. However, by combining HPMCP HP-55 and Na2CO3 as release rate modifiers, the pH dependency of the release rate was significantly reduced and improved compared to RINVOQ tablets.

[0168] [Table 19]

[0169] Example 8: Examination of the effect of manufacturing process on drug release of tablets containing anionic polymer and basic pH modifier A wet granulation compression method was also used to prepare 30 mg upadacitinib tablets containing HPMCP HP-55 and Na2CO3 as release rate modifiers. Tablet formulation E5 was prepared using the same composition as formulation E4 using a wet granulation compression method. Upadacitinib 15.36 g, HPMC K4M 15 g, HPMCP HP-55 20 g, sodium carbonate monohydrate 10 g, and Avicel 101 15.10 g were each first sieved and dry mixed in a benchtop high-speed mixer, then granulated with approximately 32 g of water. The wet granulation was dried under vacuum at 60° C. overnight. The dried granulation was sieved through a 30 mesh screen and blended with the extragranular excipients in Table 16 in a Turbula blender (49 rpm) for approximately 5 minutes. This powder blend was then mixed with magnesium stearate for 2 minutes and then compressed into 200 mg oval tablets in a Carver press, each tablet containing 30 mg of upadacitinib (anhydrous form).

[0170] [Table 20]

[0171] The in vitro dissolution rate of Formulation E5 was determined using USP 1 method in 900 ml of (1) 0.1 N HCl, (2) 50 mM phosphate buffer (pH 6.8), each at 100 rpm and 37° C. At least three tablets were used under each test condition. The results of dissolution testing of tablets made by wet granule compression and direct compression methods are shown in Table 17 and FIG. 15, respectively. These data indicate that the pH dependence of upadacitinib release from hydrophilic matrix tablets containing dual release rate modifiers can be further minimized using the wet granule compression method, resulting in pH-independent release.

[0172] [Table 21]

[0173] Example 9: pH-independent release of upadacitinib from hydrophilic matrices by modulating the release surface area Upadacitinib ER hydrophilic matrix tablets (Formulation E6) with reduced pH dependency similar to RINVOQ tablets were prepared using an acidic release rate modifier and direct compression. To further reduce the pH dependency of drug release or to allow pH independent release, a barrier layer was applied to a portion of the tablet surface using a pH dependent polymer. Two types of barrier formulations were used: (1) Repeated application of a pH dependent polymer coating solution to one side of the tablet surface (Formulation E7) and (2) Application of a pH dependent layer to one side of the tablet surface by compression coating (Formulation E8).

[0174] The composition and preparation of the reference and test tablets are described in the following sections.

[0175] Part A: Preparation of reference ER core tablets (Formulation E6) Upadacitinib ER hydrophilic matrix tablets, formulation E6 (Lot: S-211004-korecsa-073), were prepared using direct compression. The materials shown in Table 18 were each weighed and sieved through a 30 mesh screen prior to blending. The drug and all excipients, except for sodium stearyl fumarate, were first blended in a Turbula blender at 49 rpm for 5 minutes, followed by addition of sodium stearyl fumarate and mixing for an additional 2 minutes. The final blend was compressed into monolithic 200 mg tablets (reference tablets) using an oval die at 3000 lbs force in a Carver press. Each tablet contains 30 mg of upadacitinib (anhydrous form).

[0176] Part B: Preparation of film coating solution A 5% (w / w) coating solution was prepared by mixing 4.5 g of HPMCAS LG and 0.5 g of PEG 3350 in acetone / water (90 / 10) with stirring until completely dissolved.

[0177] Part C: Preparation of Compression Coating Layer Blends HPMCAS (LG), 9.2 g, Fastflo Lactose, 0.75 g were sieved through a 35 mesh screen and blended in a Turbula blender (49 rpm) for approximately 5 minutes. This powder blend was then blended with Magnesium Stearate, 0.05 g, for an additional 2 minutes.

[0178] Part D: Preparation of partially coated ER tablets using the solvent method (Formulation E7) The application of the barrier layer was carried out as follows: each tablet was first fitted on the tip of a pair of tweezers. The coating solution was applied to one side of the tablet surface by repeated immersion and air drying for 4 minutes. This process was repeated 10 times. After the dip coating process was completed, the tablets were placed in a 40°C oven for at least 24 hours before dissolution testing. The total weight gain per tablet after coating / drying is approximately 8 mg.

[0179] Part E: Preparation of partially coated ER tablets using compression coating method (Formulation E8) Bilayer tablets of Formulation E8 were prepared in a Carver press as follows: 200 mg of Formulation E6 blend was filled into an oval mold die cavity, which was then subjected to low tamping force by the upper punch followed by 40 mg of compression coat layer blend, which was then compressed at approximately 3000 lbs. Each tablet contains 30 mg of upadacitinib (anhydrous form).

[0180] [Table 22]

[0181] Part F: Dissolution testing of formulations E6, E7 and E8.

[0182] The in vitro dissolution rates of the test tablets and the reference tablets were determined using USP 1 method at 150 rpm in (1) 25 mM phosphate buffer (pH 6.8) containing 2.7% NaCl, and (2) 900 ml of 0.1 N HCl, respectively, at 37° C. At least three tablets were used under each test condition. The dissolution test results are shown in Table 19. Figure 16 shows the comparative dissolution profiles of Formulations E6 and E7; Figure 17 shows the comparative dissolution profiles of Formulations E6 and E8. The results from these figures show that the moderate pH dependence of the release rate of the reference tablets can be essentially eliminated by applying a pH-dependent barrier layer to a portion of the tablet surface using either a solvent-based coating or a compression coating process.

[0183] [Table 23]

[0184] Example 10: pH-independent release of upadacitinib using osmotic pump tablets Upadacitinib ER tablets were prepared using an osmotic pump delivery system. The final dosage form consisted of a single-layered, bi-layered or tri-layered core containing an osmotic agent (osmogent) coated with a semipermeable membrane. Orifices were formed by mechanically drilling the tablet surface of the drug layer to facilitate drug release.

[0185] The formulations and processes for preparing the different osmotic pump tablets are summarized in the following sections.

[0186] Part I: Preparation of drug layer blend and push layer blend Drug Layer Blend A: Upadacitinib 7.68 g, sorbitol (Neosorb P60W) 21.32 g, polyethylene oxide (polyox WSR N-80N) 20 g, sodium chloride (micronized) 20 g, fumaric acid 25 g, and HPC (Klucel EXF) 5 g were sieved through a 30 mesh screen and blended in a Turbula blender (49 rpm) for approximately 5 minutes. This powder blend was then mixed with magnesium stearate 1 g for an additional 2 minutes.

[0187] Drug Layer Blend B: Upadacitinib 0.768 g, sorbitol (Neosorb P60W) 2.132 g, polyethylene oxide (polyox WSR N-80N) 2.0 g, sodium chloride (micronized) 2.0 g, lactose 2.5 g, HPC (Klucel EXF) 0.5 g were sieved through a 30 mesh screen and blended in a Turbula blender (49 rpm) for approximately 5 minutes. This powder blend was then mixed with magnesium stearate 0.1 g for an additional 2 minutes.

[0188] Push layer blend: 60 g HEC (Natrosol, 250 HX), 20 g Sorbitol (Neosorb P60W), 16 g Sodium Chloride (micronized), 3.0 g HPC (Klucel EXF) were sieved through a 30 mesh screen and mixed in a Turbula blender (49 rpm) for approximately 5 minutes. This powder blend was then mixed with 1 g Magnesium Stearate for an additional 2 minutes.

[0189] The formulation compositions of the drug layer and push layer are shown in Table 20.

[0190] [Table 24]

[0191] Part II: Preparation of monolithic layer tablets (Formulation E9).

[0192] Monolithic layer core tablets were prepared in a Carver press as follows: 150 mg of drug layer blend and 150 mg of push layer blend were weighed, mixed thoroughly, and then filled into the die cavity using an 8 mm round convex tooling and compressed into a finished tablet at approximately 3000 lbs of force. The final core tablet weight was 300 mg containing 11.25 mg of upadacitinib (anhydrous form).

[0193] Part III: Preparation of bilayer tablet A (Formulation E10) Bilayer core tablets were prepared in a Carver press as follows: 150 mg of drug layer A blend and push layer blend were weighed separately. The drug layer blend was first filled into the die cavity using an 8 mm round convex die, then gently tamped with an upper punch, and then the push layer was added on top of the drug layer, and a final compression force of approximately 3000 lbs was applied to form a bilayer tablet. The final core tablet weight was 300 mg containing 11.25 mg of upadacitinib (anhydrous form).

[0194] Part IV: Preparation of trilayer tablets (Formulation E11) Tri-layer core tablets were prepared in a Carver press as follows: 150 mg of drug layer blend, 150 mg of push layer blend, and Separating layer (ethyl cellulose) 25mg were weighed separately. The drug layer blend was first filled into the die cavity using a 6 mm round convex die, followed by gentle tamping with the upper punch, then the push layer was added on top of the drug layer, followed by another gentle tamping, and finally the push layer was added to the top of the separatory chamber. A final compression force of approximately 3000 lbs was applied to form the tri-layer tablet. The final core tablet weight was 325 mg containing 11.25 mg of upadacitinib (anhydrous form).

[0195] Part V: Preparation of bilayer tablet B (Formulation E12) Bilayer core tablets were prepared in a Carver press as follows: 150 mg of drug layer B blend and push layer blend were weighed separately. The drug layer blend was first filled into the die cavity using an 8 mm round convex die, followed by gentle tamping with an upper punch, and then the push layer was added on top of the drug layer, and a final compression force of approximately 3000 lbs (about 1360.8 kg) was applied to form a bilayer tablet. The final core tablet weight was 300 mg containing 11.25 mg of upadacitinib (anhydrous form).

[0196] Part VI: Preparation of coating solutions The solvent for the coating solution was prepared by weighing 98 g of acetone and 2 g of water into a beaker and mixing thoroughly. A 5% (w / w) dip coating solution was prepared by slowly adding 5 g of Opadry CA (Colorcon, Fully Formulated Osmotic Coating System 500F 190012 Clear) to 95 g of a 98 / 2 acetone / water solution and mixing until the solution was clear.

[0197] Part VII: Preparation of coated tablets for dissolution testing The core tablets of formulations E9, E10, E11 and E12 were first fitted into the sharp tip of the forceps. The entire tablet was then immersed in the coating solution and then air-dried for 4 minutes. This operation was repeated 25 times. After the application of the coating film was completed, the tablets were transferred to a 40°C oven and dried for at least 24 hours. After drying, the tablets were weighed and the coating weight gain was calculated. The average weight gain after drying of formulations E9, E10, E11 and E12 was 46.5 mg, 41.7 mg, 46.7 mg and 44.05 mg, respectively. Orifice sizes of 0.5 mm (formulation E9), 1.6 mm (formulations E10 and E12) and 2.0 mm (formulation E11) were mechanically drilled on the drug layer side near the tip of the forceps used to fit the tablets.

[0198] Part VIII: Dissolution of Coated Tablets of Formulation E9, Formulation E10, Formulation E11, and Formulation E12 The in vitro dissolution rates of the osmotic pump tablets were determined using USP 1 method at 100 rpm in (1) 50 mM phosphate buffer (pH 6.8) and 900 ml of 0.1 N HCl (pH 1.2), respectively, at 37° C. At least three tablets were used under each test condition. The results of the dissolution tests are shown in Table 21. FIG. 18 shows that pH-independent and near-zero order drug release was obtained for all three formulations. FIG. 19 shows that pH-independent and near-zero order drug release can be achieved using the same product design, regardless of the presence of an acidic release rate modifier (such as fumaric acid).

[0199] [Table 25]

[0200] Other embodiments This application references various issued patents, published patent applications, journal articles and other publications, each of which is incorporated herein by reference.

[0201] The foregoing describes several non-limiting embodiments of the present disclosure. Those skilled in the art will appreciate that various changes and modifications can be made to this specification without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

1. A sustained release solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one pH-dependent polymer, and at least one release-controlling material.

2. 2. The sustained release solid dosage form of claim 1, wherein the at least one pH-dependent polymer and the at least one release-controlling material comprise a matrix system containing upadacitinib or a pharma- ceutically acceptable salt thereof.

3. 3. The sustained release solid dosage form of claim 1 or 2, which does not include an enteric film coat.

4. The sustained release solid dosage form according to any one of claims 1 to 3, wherein the at least one pH-dependent polymer is an enteric polymer or an anionic polysaccharide.

5. The sustained release solid dosage form according to any one of claims 1 to 4, wherein the at least one pH-dependent polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or alginic acid.

6. at least one pH-dependent polymer is present in an amount of 20% to 40% w / w of the solid dosage form; and The extended release solid dosage form of any one of claims 1 to 5, wherein the at least one release controlling material is present in an amount of 30% to 60% w / w of the solid dosage form.

7. The sustained release solid dosage form of any one of claims 1 to 6, further comprising a basic pH adjusting agent.

8. 8. The sustained release solid dosage form of claim 7, wherein the basic pH adjusting agent is sodium carbonate, meglumine or trisodium phosphate dodecahydrate.

9. 1. A sustained release solid dosage form comprising upadacitinib or a pharma- ceutical acceptable salt thereof, at least one release rate modifier, and at least one release controlling material, (a) the at least one release rate modification agent comprises an ion exchange resin; or (b) The extended release solid dosage form, wherein the at least one release rate modification agent comprises a basic pH modifying agent, and the extended release solid dosage form further comprises an anionic polymer. (a) the ion exchange resin comprises a sulfonated copolymer comprising styrene and divinylbenzene; or 10. The sustained release solid dosage form of claim 9, wherein (b) the basic pH adjusting agent is sodium carbonate, meglumine, or trisodium phosphate dodecahydrate.

11. The extended release solid dosage form of claim 9, wherein upadacitinib or a pharma- ceutically acceptable salt thereof and the ion exchange resin form an upadacitinib-ion exchange resin complex, the upadacitinib-ion exchange resin complex comprising upadacitinib, or a pharma- ceutically acceptable salt thereof, bound to the ion exchange resin.

12. 10. The sustained release solid dosage form of claim 9, wherein the basic pH adjusting agent is present in an amount of 5% to 20% w / w.

13. a core comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one release rate modifier, and at least one release controlling material; and A barrier layer partially covering the core 16. A sustained release solid dosage form comprising:

14. At least one release rate modifier is an acidic pH modifier; and / or The sustained release solid dosage form of claim 13 , wherein the barrier layer comprises a pH-dependent polymer.

15. 15. The sustained release solid dosage form of claim 14, wherein the pH-dependent polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS). (a) containing less than 10% by weight of a hygroscopic acidic pH adjuster; or (b) the sustained release solid dosage form of any one of claims 1 to 15, which is substantially free of a hygroscopic acidic pH adjusting agent.

17. 17. The sustained release solid dosage form of claim 16, wherein the hygroscopic acidic pH adjusting agent is an organic acid.

18. 18. The sustained release solid dosage form of claim 17, wherein the organic acid is selected from the group consisting of tartaric acid, citric acid and maleic acid.

19. The sustained release solid dosage form according to any one of claims 1 to 18, wherein at least one release controlling material is a release controlling polymer.

20. 20. The sustained release solid dosage form of any one of claims 1 to 19, wherein the at least one release controlling polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, hydroxyethyl cellulose, copolymers of acrylic acid crosslinked with polyalkenyl polyethers (Carbopol), non-ionic homopolymers of ethylene oxide (Polyox), water soluble natural gums of polysaccharides, crosslinked starch, polyvinyl acetate, polyvinylpyrrolidone and combinations thereof.

21. 21. The extended release solid dosage form of any one of claims 1 to 20, wherein the solid dosage form further comprises one or more additional excipients selected from the group consisting of fillers, binders, glidants, lubricants, film coats, and combinations thereof; and wherein the one or more additional excipients are present in an amount of less than 50% w / w of the solid dosage form.

22. a core comprising upadacitinib or a pharma- ceutically acceptable salt thereof; a semipermeable membrane covering the core, the semipermeable membrane being permeable to aqueous fluids and substantially impermeable to upadacitinib; and at least one drug delivery orifice that provides a passageway through which upadacitinib, or a pharma- ceutically acceptable salt thereof, may be released from the core to an environment external to the sustained release solid dosage form; 16. A sustained release solid dosage form comprising:

23. 23. The sustained release solid dosage form of claim 22, wherein the core further comprises an osmogent.

24. 24. The sustained release solid dosage form of claim 23, wherein the osmagenta comprises a water soluble salt of an inorganic acid, an osmotic polymer, a carbohydrate, or a combination thereof.

25. (a) the core is single-layered or multi-layered; or The sustained release solid dosage form of any one of claims 22 to 24, wherein (b) the core comprises a push layer.

26. (a) the push layer comprises an osmotic polymer; and / or 26. The sustained release solid dosage form of claim 25, wherein (b) the semipermeable membrane comprises cellulose acetate (CA).

27. The sustained release solid dosage form of claim 26, wherein the osmotic polymer is hydroxyethyl cellulose (HEC).

28. 1. A stable solid dosage form comprising upadacitinib or a pharma- ceutically acceptable salt thereof, at least one pH-dependent polymer, and at least one controlled release material, wherein at an initial time point, less than or equal to 0.2% w / w of upadacitinib degradation products are present in the solid dosage form, and at a time point after storage, less than or equal to 0.5% w / w of upadacitinib degradation products are present in the solid dosage form; the initial and post-storage time points being at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months apart, during which the composition is at 25° C.±2° C. and 60%±5% relative humidity; A solid dosage form, wherein an upadacitinib degradation product is (3S,4R)-3-ethyl-4-(3-(hydroxymethyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

29. 30. The stable solid dosage form of claim 28, wherein the at least one pH-dependent polymer is an enteric polymer or an anionic polysaccharide.

30. 30. The stable solid dosage form of claim 29, wherein the at least one pH-dependent polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or alginic acid.

31. (a) 56% to 94% of upadacitinib is released from the solid dosage form over 4 hours in 900 ml of 0.1 N HCl (pH 1.1) at 37°C and a rotation speed of 150 rpm using USP I method; or 68%-100% of the upadacitinib is released from the solid dosage form in 900 ml of 0.1 N HCl (pH 1.1) at 37°C and a rotation speed of 150 rpm using USP I method; or or 75%-100% of the upadacitinib is released from the solid dosage form in 900 ml of 0.1 N HCl (pH 1.1) at 37°C with a rotation speed of 150 rpm using USP I method; or (b) 41%-68% of upadacitinib is released from the solid dosage form over 4 hours in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37° C. and a rotation speed of 150 rpm using USP I method; or 51%-85% of upadacitinib is released from the solid dosage form in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37° C. using USP I method at 150 rpm; or or 59%-99% of the upadacitinib is released from the solid dosage form in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) containing 2.75% sodium chloride at 37°C and a rotation speed of 150 rpm using USP I method; or (c) 49%-81% of upadacitinib is released from the solid dosage form over 4 hours in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) at 37° C. and a rotation speed of 150 rpm using USP I method; or 60%-100% of the upadacitinib is released from the solid dosage form in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) at 37°C and a rotation speed of 150 rpm using USP I method; or or 67%-100% of the upadacitinib is released from the solid dosage form in 900 ml of 0.025 M sodium phosphate buffer (pH 6.8) at 37°C and a rotation speed of 150 rpm using USP I method; or (d) 47%-79% of upadacitinib is released from the solid dosage form in 900 ml of 0.050 M sodium phosphate buffer (pH 6.8) at 37° C. and a rotation speed of 150 rpm using USP I method; or or 58%-96% of upadacitinib is released from the solid dosage form in 900 ml of 0.050 M sodium phosphate buffer (pH 6.8) at 37°C and a rotation speed of 150 rpm using USP I method; or 31. The stable solid dosage form of any one of claims 28-30, wherein 65%-100% of the upadacitinib is released from the solid dosage form in 8 hours using USP I method in 900 ml of 0.050 M sodium phosphate buffer, pH 6.8, at 37°C and a rotation speed of 150 rpm.

32. The extended release solid dosage form of any one of claims 1 to 27 or the stable solid dosage form of any one of claims 28 to 31, wherein upadacitinib or a pharma- ceutically acceptable salt thereof is present in the solid dosage form in an amount sufficient to deliver 5 mg to 50 mg of upadacitinib free base equivalent per dosage unit.

33. The solid dosage form after storage is (a) pharma- ceutically acceptable levels of degradation products of upadacitinib, and / or (b) maintains a dissolution profile after storage substantially similar to the initial dissolution profile; 28. The sustained release solid dosage form according to any one of claims 1 to 27.

34. the solid dosage form contains 0.5% w / w or less of upadacitinib degradation products after storage of the solid dosage form; The shelf life of the solid dosage form is 6 months, 12 months, 18 months, 24 months, 30 months or 36 months; 34. The sustained release solid dosage form of claim 33.

35. The extended release solid dosage form of claim 33 or claim 34, wherein an upadacitinib degradation product is (3S,4R)-3-ethyl-4-(3-(hydroxymethyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

36. Storage of the solid dosage form is at 25° C.±2° C. and 60%±5% relative humidity for between 3 months and 48 months, 6 months and 36 months, or 12 months and 24 months; 36. The sustained release solid dosage form according to any one of claims 33 to 35.

37. an initial dissolution profile of less than or equal to 85% of the upadacitinib released from the solid dosage form in 1 or 2 hours, between 10% and 65% of the upadacitinib released from the solid dosage form in 2 hours, between 35% and 90% of the upadacitinib released from the solid dosage form in 4 hours, and / or between 70% and 100% of the upadacitinib released from the solid dosage form in 10 hours; and 37. The sustained release solid dosage form according to any one of claims 33 to 36, wherein the initial dissolution profile is measured in 900 mL of (1) 0.025 M sodium phosphate buffer (pH 6.8), (2) 0.025 M phosphate buffer (pH 6.8), (3) 0.050 M phosphate buffer (pH 6.8), or (4) 0.1 N HCl (pH 1.1), containing 2.75% sodium chloride, at 37°C ± 2°C using a USP I apparatus with a rotation speed of 150 rpm.

38. The total weight is less than 400 mg, or 32. The sustained release solid dosage form of any one of claims 1 to 27 or the stable solid dosage form of any one of claims 28 to 31, having a total weight between 100 mg and 300 mg.

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