Pharmaceutical compositions and methods using the same

Abstract

Solid pharmaceutical compositions containing an active pharmaceutical ingredient, such as a JAK inhibitor, and methods of treatment using such pharmaceutical compositions are described.

Description

PHARMACEUTICAL COMPOSITIONS AND METHODS USING THE SAME TECHNICAL FIELD

[0001] The present disclosure is directed to various pharmaceutical compositionscontaining an active pharmaceutical ingredient, such as a JAK inhibitor, and methods of treatment using such pharmaceutical compositions. BACKGROUND

[0002] Solid pharmaceutical compositions such as compressed tablets are a common typeof oral dosage form that is used in both human clinical and veterinary medicine. The manufacture of solid pharmaceutical compositions containing certain active pharmaceutical ingredients can present challenges when the active pharmaceutical ingredient is incorporated at a low concentration. When the active pharmaceutical ingredient represents a small percentage of the batch mix, achieving a relatively homogeneous or uniform ingredient can be difficult. Accordingly, there remains a need for improved low concentration API pharmaceutical compositions that can be produced with high batch uniformity.

[0003] Further, in veterinary applications, such as in oral treatments for companionanimals, solid pharmaceutical compositions need to be sufficiently soft such that an animal can comminute the composition. Various factors such as storage conditions and storage time can affect composition hardness. As such, there remains a need for solid pharmaceutical compositions that maintain stable hardness characteristics over a wide range of storage conditions and prolonged storage time. SUMMARY

[0004] The present disclosure is directed to various processes for the preparingcompositions containing an active pharmaceutical ingredient, such as a JAK inhibitor, and methods of treatment using such pharmaceutical compositions. In aspects, the compositions are solid pharmaceutical compositions.

[0005] In some embodiments, a solid pharmaceutical composition is provided,comprising, consisting essentially of, or consisting of an active pharmaceutical ingredient; and at least one excipient, wherein the solid pharmaceutical composition has a tensile strength fromabout 0.5 MPa to about 5 MPa when compressing a mixture comprising the active pharmaceutical ingredient and at least one excipient with a compression pressure from about 50 MPa to about 450 MPa.

[0006] In some embodiments, a pharmaceutical composition is provided, comprising: acore comprising, consisting essentially of, or consisting of an active pharmaceutical ingredient, dicalcium phosphate dihydrate, and at least one excipient; and optionally a polymeric coating comprising a polymeric material coating at least a portion of the core, wherein a coating process is run at an environmental equivalency factor from 1 to 5 and the pharmaceutical composition has a loss on drying less than or equal to 4% (w / w).

[0007] The present disclosure provides for various processes for preparing a solidpharmaceutical composition of a low concentration active pharmaceutical ingredient. For example, the process can comprise, consist essentially of, or consist of: mixing the active pharmaceutical ingredient with at least one excipient to provide a mixture; optionally disaggregating the mixture; and compressing the mixture to form the solid pharmaceutical composition, wherein the solid pharmaceutical composition comprises from about 0.1% to about 50% (w / w), about 1% to about 40% (w / w), about 0.1% to about 15% (w / w), from about 0.5% to about 10% (w / w), from about 1.0% to about 5% (w / w), or from about 1.0% to about 3% (w / w) of the active pharmaceutical ingredient; wherein the solid pharmaceutical composition has a tensile strength from about 0.5 MPa to about 5 Mpa when compressing the mixture with a compression pressure from about 50 Mpa to about 450 Mpa; and wherein the mixture has a blend uniformity from 75% to 125% of an average content of the active pharmaceutical ingredient in a single batch or a plurality of batches prepared by the process and / or wherein the solid pharmaceutical composition has a content uniformity from 75% to 125% of an average content of the active pharmaceutical ingredient in a single batch or a plurality of the solid pharmaceutical compositions prepared by the process.

[0008] The present disclosure further provides for various processes for preparing astorage stable composition, for example, a solid stabile pharmaceutical composition. For example, the process can comprise, consist essentially of, or consist of: mixing an active pharmaceutical ingredient with at least one excipient and dicalcium phosphate dihydrate to form a mixture; compressing pressing the mixture into the solid pharmaceutical composition; heatingthe solid pharmaceutical composition at a temperature of from about 40 °C to about 80 °C; andcoating the heated solid pharmaceutical composition with a polymeric material to produce the coated solid pharmaceutical composition, wherein a coating process is run at an environmental equivalency factor from 1 to 5.

[0009] As noted, the present disclosure provides for various compositions, for example,stabile solid pharmaceutical compositions. For instance, a solid pharmaceutical composition can comprise, consist essentially of, or consist of a core comprising: an active pharmaceutical ingredient (API), dicalcium phosphate dihydrate, and at least one excipient; and a polymeric coating comprising a polymeric material coating at least a portion of the core, wherein a coating process is run at an environmental equivalency factor from 1 to 5 and the solid pharmaceutical composition has a loss on drying less than or equal to 4% (w / w).

[0010] The present disclosure also provides for methods of treating a dermatologicalcondition (e.g., allergic dermatitis, atopic dermatitis, pruritus, etc.) comprising, consisting essentially of, or consisting of, for example, administering to a non-human mammal in need thereof a solid pharmaceutical composition as disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1A depicts tablet hardness, thickness, and LOD and water content by KF for2.4 mg tablet batch B1907-000129 (Coated Tablet, with and without desiccant) during the stability study for the initial batches (Example 2). Hardness [N] is shown in green. Thickness [mm] is shown in purple. LOD [%] is shown in blue. Water content KF [%] is shown in red.

[0012] FIG. 1B depicts hardness, thickness, and LOD and water content by KF for 16 mgtablet batch B1907-000130 (coated tablet) during the stability study for the initial batches (Example 2). Hardness [N] is shown in green. Thickness [mm] is shown in purple. LOD [%] is shown in blue. Water content KF [%] is shown in red.

[0013] FIG. 2A depicts Test Formulation Tablet hardness / thickness and water content(by KF and LOD) – 4.8 mg dose strength in blisters (BLI) and bottles (BOT) at 25°C / 60%RH. Hardness [N] is shown in green. Thickness [mm] is shown in purple. Water content KF [%] is shown in blue. LOD [%] is shown in red.

[0014] FIG. 2B depicts Test Formulation Tablet hardness / thickness and water content(by KF and LOD) – 15 mg dose strength in blisters (BLI) and bottles (BOT) at 25°C / 60%RH.Hardness [N] is shown in green. Thickness [mm] is shown in purple. Water content KF [%] is shown in blue. LOD [%] is shown in red.

[0015] FIG. 2C depicts Test Formulation Tablet hardness / thickness and water content(by KF and LOD) – 4.8 mg dose strength in blisters (BLI) and bottles (BOT) at 40°C / 75%RH. Hardness [N] is shown in green. Thickness [mm] is shown in purple. Water content KF [%] is shown in blue. LOD [%] is shown in red.

[0016] FIG. 2D depicts Test Formulation Tablet hardness / thickness and water content(by KF and LOD) – 15 mg dose strength in blisters (BLI) and bottles (BOT) at 40°C / 75%RH. Hardness [N] is shown in green. Thickness [mm] is shown in purple. Water content KF [%] is shown in blue. LOD [%] is shown in red.

[0017] FIG. 3 is an exemplary flowchart of process steps for the coating process for theilunocitinib tablets.

[0018] FIG. 4 is a description of the two processes evaluated for main-blending (beforelubrication; PS = pregelatinized starch). DETAILED DESCRIPTION

[0019] The present disclosure is directed to various pharmaceutical compositionscontaining an active pharmaceutical ingredient, such as a Janus Kinase (JAK) inhibitor, and methods of treatment using such pharmaceutical compositions. Processes for Preparing Solid Pharmaceutical Compositions

[0020] As noted, various processes for preparing a solid pharmaceutical composition of alow concentration active pharmaceutical ingredient are provided herein. It has been discovered that solid pharmaceutical compositions having a low concentration of an active pharmaceutical ingredient, such as a JAK inhibitor can be prepared with high uniformity according to the processes described herein. JAK inhibitors, as referred to herein, can include, for example, JAK1 inhibitors and / or JAK inhibitors comprising a pyrrolopyrimidine or pyrrolopyridine scaffold. In particular, the JAK inhibitor can comprise ilunocitinib (2-[1-cyclopropylsulfonyl-3- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]4zetidine-3-yl]acetonitrile) or a pharmaceutically acceptable salt thereof. In any embodiment, the JAK inhibitor may consist or consist essentially of ilunocitinib or a pharmaceutically acceptable salt thereof.

[0021] Advantageously and unexpectedly, the processes described herein do not requiregranulation techniques to ensure sufficient mixing and uniformity despite a low concentration of active pharmaceutical ingredients. As such, in various embodiments, the process may comprise no granulation step. Accordingly, various processes for preparing a solid pharmaceutical composition of a low concentration active pharmaceutical ingredient comprise: mixing the active pharmaceutical ingredient with at least one excipient to provide a mixture; disaggregating the mixture; and compressing the mixture to form the solid pharmaceutical composition, wherein the solid pharmaceutical composition comprises from about 0.1% to about 50% (w / w), about 1% to about 40% (w / w), about 0.1% to about 15% (w / w), from about 0.5% to about 10% (w / w), from about 1.0% to about 5% (w / w), or from about 1.0% to about 3% (w / w) of the active pharmaceutical ingredient; wherein the solid pharmaceutical composition has a tensile strength from about 0.5 MPa to about 5 MPa when compressing the mixture with a compression pressure from about 50 MPa to about 450 MPa; and wherein the mixture has a blend uniformity from 75% to 125% of an average content of the active pharmaceutical ingredient prepared by the process. As used herein, “blend uniformity” and “content uniformity” are given their usual meaning in the art. In general, “blend uniformity” refers to the homogeneity of the powder mix, and “content uniformity” refers to the homogeneity of the tablet (in instances where no coating is applied) or the core of the finished compressed tablet (in instances where coating is applied). Various apparatus and methods for sampling, sample splitting and measuring blend uniformity and content uniformity are known in the art, including cone and quartering, scoop, sampling, chute sampling, spinning riffler, table riffler, and non-invasive techniques such as near infrared spectroscopy, optical fiber spectroscopy, Raman spectroscopy, and electrical capacitance tomography. Standards, tests, assays, and other specifications generally adhere to United States Pharmacopeia (USP) and / or European Pharmacopoeia (Ph. Eur.) sampling procedures and Food and Drug Administration (FDA) regulations and guidelines. (See, e.g., USP "905# content uniformity test methodology.)

[0022] Further, various processes for preparing a storage stable solid pharmaceuticalcompositions exhibiting consistent hardness characteristics are provided herein. It has been found that the use of certain excipients (e.g., dicalcium phosphate dihydrate) provides for enhanced compressibility to for stable solid pharmaceutical compositions manufactured via direct compression. It has been further found that these excipients can interact with other ingredients orresidual / crystal water in the composition at elevated temperatures and can cause an increase in hardness characteristics of the compositions. Applicants have unexpectedly discovered that various processes described herein can provide for solid pharmaceutical compositions that maintain stable hardness characteristics over a wide range of storage conditions (e.g., elevated temperature) and prolonged storage time.

[0023] The present disclosure further provides for various processes for preparing acoated solid pharmaceutical composition. For example, the process can comprise: mixing an active pharmaceutical ingredient with at least one excipient and dicalcium phosphate dihydrate to form a mixture; compressing pressing the mixture into the solid pharmaceutical composition;heating the solid pharmaceutical composition at a temperature of from about 40 °C to about80°C; and coating the heated solid pharmaceutical composition with a polymeric material to produce the coated solid pharmaceutical composition, wherein a coating process is run at an environmental equivalency factor from 1 to 5. As used herein, “environmental equivalency factor” (EEF) is given its customary meaning in the field of tablet manufacturing. See Ebey, G. C. (1987), A thermodynamic model for aqueous film-coating, Pharm Technol, 11(4), 40–50; see also Strong J. C. (2009), Psychrometric analysis of the environmental equivalency factor for aqueous tablet coating, AAPS PharmSciTech, 10(1), 303–09 the contents of which are incorporated by reference in their entirety.

[0024] As noted, various processes described can comprise disaggregating the mixture.Disaggregating the mixture may comprise sieving the mixture through at least one sieve. The at least one sieve may have a pore diameter in the range of from about 100 µm or greater. Alternatively, the at least one sieve may have a pore diameter in the range of from about 1000 µm or smaller.

[0025] In some embodiments, the at least one sieve may have a pore diameter in therange of from about 100 µm to about 2000 µm, from about 100 µm to about 1000 µm, from about 150 µm to about 1000 µm, from about 200 µm to about 1000 µm, from about 200 µm to about 950 µm, from about 200 µm to about 900 µm, from about 200 µm to about 850 µm, from about 200 µm to about 800 µm, from about 200 µm to about 750 µm, from about 250 µm to about 750 µm, from about 300 µm to about 750 µm, from about 350 µm to about 750 µm, from about 400 µm to about 750 µm, from about 400 µm to about 700 µm, from about 400 µm toabout 650 µm, from about 400 µm to about 600 µm, from about 400 µm to about 550 µm, from about 450 µm to about 550 µm, or from about 450 µm to about 500 µm.

[0026] In another embodiment, the at least one sieve may have a pore diameter of at leastabout 100 µm, at least about 200 µm, at least about 300 µm, at least about 400 µm, at least about 450 µm, at least about 500 µm, at least about 550 µm, at least about 600 µm, at least about 700 µm, at least about 800 µm, at least about 900 µm, at least about 1000 µm, or at least about 2000 µm. In other embodiments, the at least one sieve may have a pore diameter of no more than about 100 µm, no more than about 200 µm, no more than about 300 µm, no more than about 400 µm, no more than about 450 µm, no more than about 500 µm, no more than about 550 µm, no more than about 600 µm, no more than about 700 µm, no more than about 800 µm, no more than about 900 µm, no more than about 1000 µm, or no more than about 2000 µm.

[0027] As noted, a mixture of ingredients is compressed to form the solid pharmaceuticalcomposition. In various embodiments, the average tensile strength of the composition can be about 0.1 MPa to about 10 MPa when compressing the mixture with a compression pressure from about 10 MPa to about 1000 MPa. In various embodiments, the solid pharmaceutical composition has a tensile strength from about 0.5 MPa to about 5 MPa when compressing the mixture with a compression pressure from about 50 MPa to about 450 MPa. For example, the average tensile strength with a compression pressure from about 10 MPa to about 1000 MPa may range from about 0.1 MPa to about 9 MPa, from about 0.1 MPa to about 8 MPa, from about 0.1 MPa to about 7 MPa, from about 0.1 MPa to about 6 MPa, from about 0.1 MPa to about 5 MPa, from about 0.1 MPa to about 4 MPa, from about 0.1 MPa to about 3 MPa, from about 0.1 MPa to about 2 MPa, from about 0.1 MPa to about 1 MPa, from about 0.1 MPa to about 0.5 MPa, from about 0.5 MPa to about 10 MPa, from about 1 MPa to about 10 MPa, from about 2 MPa to about 10 MPa, from about 3 MPa to about 10 MPa, from about 4 MPa to about 10 MPa, from about 5 MPa to about 10 MPa, from about 6 MPa to about 10 MPa, from about 7 MPa to about 10 MPa, from about 8 MPa to about 10 MPa, or even from about 9 MPa to about 10 MPa.

[0028] In certain embodiments, the solid pharmaceutical composition may have a tensilestrength from 1 MPa to 3 MPa when compressing the mixture with a compression pressure from 150 MPa to 200 MPa. That is, the average tensile strength with a compression pressure from about 150 MPa to about 200 MPa may range from about 1 MPa to about 2.5 MPa, from about 1MPa to about 2 MPa, from about 1 MPa to about 1.5 MPa, from about 1.5 MPa to about 3 MPa, from about 2 MPa to about 3 MPa, or even from about 2.5 MPa to about 3 MPa.

[0029] Various processes described herein can provide for solid pharmaceuticalcompositions and precursor ingredients mixtures thereof having an enhanced uniformity of active pharmaceutical ingredients. In any embodiment, the blend uniformity may range from, at the lower bound, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90% 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% to, at the upper bound, 100.1%, 100.5%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, or 130%. It is expressly envisioned that a range of the blend uniformity may be from any lower bound recited herein to any upper bound recited herein. For example, and without limitation, the blend uniformity may be from 75% to 125% or even 85% to 115% of an average content of the active pharmaceutical ingredient in a single batch or a plurality of batches prepared by the process.

[0030] Further, in any embodiment, the content uniformity may range from, at the lowerbound, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90% 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% to, at the upper bound, 100.1%, 100.5%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, or 130%. It is expressly envisioned that a range of the content uniformity may be from any lower bound recited herein to any upper bound recited herein. For example, and without limitation, the content uniformity may be from 75% to 125% or even 85% to 115% of an average content of the active pharmaceutical ingredient in a single batch or a plurality of solid pharmaceutical compositions prepared by the process.

[0031] The processes described herein may further comprise heating and coating steps.For example, the processes can comprise heating the solid pharmaceutical composition at atemperature of from about 40 °C to about 80 °C or from about 40 °C to about 70 °C; and coatingthe heated solid pharmaceutical composition with a polymeric material to produce the coated solid pharmaceutical composition, wherein the coating process is run at an environmentalequivalency factor from 1 to 5. The composition may be heated to a temperature of about 40 °C,about 41 °C, about 42 °C, about 43 °C, about 44 °C, about 45 °C, about 46 °C, about 47 °C, about48 °C, about 49 °C, about 50 °C, about 51 °C, about 52 °C, about 53 °C, about 54 °C, about55 °C, about 56 °C, about 57 °C, about 58 °C, about 59 °C, about 60 °C, about 61 °C, about62 °C, about 63 °C, about 64 °C, about 65 °C, about 66 °C, about 67 °C, about 68 °C, about69 °C, about 70 °C, about 71 °C, about 72 °C, about 73 °C, about 74 °C, about 75 °C, about76 °C, about 77 °C, about 78 °C, about 79 °C, or about 80 °C. That is, the composition may beheated to a temperature from about 40°C to about 65°C, from about 40°C to about 60°C, from about 40°C to about 55°C, from about 40°C to about 50°C, from about 40°C to about 45°C, from about 45°C to about 80°C, from about 50°C to about 80°C, from about 55°C to about 80°C, from about 60°C to about 80°C, from about 65°C to about 80°C, from about 70°C to about 80°C, or even from about 75°C to about 80°C. The coating process of the composition may be run at an environmental equivalency factor of about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5. That is, the composition’s environmental equivalency factor may be from about 1 to about 5, from about 1.3 to about 5, from about 1.5 to about 4, from about 2 to about 4, from about 2 to about 3.5, from about 1.4 to about 2.8, from about 2.4 to about 3.8, from about 2.4 to about 2.8, from about 2 to about 3.4, from about 2 to about 3.3, from about 2 to about 3.2, from about 2 to about 3.1, from about 2 to about 3, from about 2 to about 2.9, from about 2 to about 2.8, from about 2 to about 2.7, from about 2 to about 2.6, from about 2 to about 2.5, from about 2 to about 2.4, from about 2 to about 2.3, from about 2 to about 2.2, from about 2 to about 2.1, from about 2.3 to about 2.6, from about 2.1 to about 3.5, from about 2.2 to about 3.5, from about 2.3 to about 3.5, from about 2.4 to about 3.5, from about 2.6 to about 3.5, from about 2.2 to about 3.5, from about 2.7 to about 3.5, from about 2.8 to about 3.5, from about 2.9 to about 3.5, from about 3 to about 3.5, from about 3.1 to about 3.5, from about 3.2 to about 3.5, from about 3.3 to about 3.5, or even from about 3.4 to about 3.5.

[0032] In any embodiment, the coating step may comprise spraying the solidpharmaceutical composition with the polymeric material; drying the sprayed solid pharmaceutical composition; and cooling the solid pharmaceutical composition.

[0033] In any embodiment, the polymeric material may comprise, for example, a graftcopolymer. The graft copolymer may comprise a polyvinyl alcohol–polyethylene glycol graft copolymer. For example, the graft copolymer may include the formulation of Opadry QX™.

[0034] In various embodiments, dicalcium phosphate dihydrate (i,e., (CaHPO4)·(H2O)2),also referred to dibasic calcium phosphate dihydrate, can be added to the mixture as described herein. Dicalcium phosphate dihydrate has been discovered to enhance stability of the solid pharmaceutical composition. In particular, this ingredient can provide for stable hardness characteristics over a wide range of storage conditions and prolonged storage time.

[0035] In any embodiment of any process of the present disclosure, the solidpharmaceutical composition may comprise about 15 wt.% or less, about 14.5 wt.% or less, about 14 wt.% or less, about 13.5 wt.% or less, about 13 wt.% or less, about 12.5 wt.% or less, about 12 wt.% or less, about 11.5 wt.% or less, about 11 wt.% or less, about 10.5 wt.% or less, about 10 wt.% or less, about 9.5 wt.% or less, about 9 wt.% or less, about 8.5 wt.% or less, about 8 wt.% or less, about 7.5 wt.% or less, about 7 wt.% or less, about 6.5 wt.% or less, about 6 wt.% or less, about 5.5 wt.% or less, about 5 wt.% or less, about 4.5 wt.% or less, about 4 wt.% or less, about 3.5 wt.% or less, about 3 wt.% or less, about 2.5 wt.% or less, about 2 wt.% or less, about 1.5 wt.% or less, about 1 wt.% or less, or about 0.5 wt.% or less of the active pharmaceutical ingredient. That is, the solid pharmaceutical composition may comprise from about 0.1 wt.% to about 15 wt.%, from about 0.1 wt.% to about 12.5 wt.%, from about 0.1 wt.% to about 10 wt.%, from about 0.1 wt.% to about 7.5 wt.%, from about 0.1 wt.% to about 5 wt.%, from about 0.1 wt.% to about 4.5 wt.%, from about 0.1 wt.% to about 4 wt.%, from about 0.1 wt.% to about 3.5 wt.%, from about 0.1 wt.% to about 3 wt.%, from about 0.1 wt.% to about 2.5 wt.%, from about 0.1 wt.% to about 2 wt.%, from about 0.1 wt.% to about 1.5 wt.%, from about 0.1 wt.% to about 1 wt.%, from about 0.1 wt.% to about 0.5 wt.%, from about 0.5 wt.% to about 3 wt.%, from about 1 wt.% to about 5 wt.%, from about 1.5 wt.% to about 5 wt.%, from about 2 wt.% to about 5 wt.%, from about 2.5 wt.% to about 5 wt.%, from about 3 wt.% to about 5 wt.%, from about 3.5 wt.% to about 5 wt.%, from about 4 wt.% to about 5 wt.%, or even from about 0.5 wt.% to about 5 wt.% of the active pharmaceutical ingredient.

[0036] In any embodiment of any process of the present disclosure, the solidpharmaceutical composition may comprise from about 1 mg to about 150 mg, from about 1 mg to about 125 mg, from about 1 mg to about 100 mg, from about 1 mg to about 95 mg, from about 1 mg to about 90 mg, from about 1 mg to about 85 mg, from about 1 mg to about 80 mg, from about 1 mg to about 75 mg, from about 1 mg to about 70 mg, from about 1 mg to about 65 mg, from about 1 mg to about 60 mg, from about 1 mg to about 55 mg, from about 1 mg to about 50mg, from about 1 mg to about 45 mg, from about 1 mg to about 40 mg, from about 2 mg to about 40 mg, from about 2 mg to about 35 mg, from about 2 mg to about 30 mg, from about 3 mg to about 30 mg, from about 3 mg to about 25 mg, from about 3 mg to about 20 mg, or even from about 4 mg to about 20 mg of the active pharmaceutical ingredient.

[0037] In any embodiment of any process of the present disclosure, the process mayfurther comprise the step of mixing into the mixture at least one additional ingredient, such as an ingredient or excipient described herein such as a filler, a disintegrant, a glidant, a lubricant, a complexing agent, a solubilizer, a stabilizer, a preservative, a surfactant, a polymer, and mixtures thereof.

[0038] In any embodiment of any process of the present disclosure, the excipient maycomprise a starch. In any embodiment of any process of the present disclosure, the excipient may comprise a pregelatinized starch. For example, the starch may comprise pregelatinized maize starch.

[0039] In any embodiment of any process of the present disclosure, the solidpharmaceutical composition may further comprise a binder. The may binder comprise at least one member selected from microcrystalline cellulose, wood cellulose, ethyl cellulose, carboxymethyl cellulose, lactose, anhydrous lactose, polyvinylpolypyrrolidone, polyvinylpyrrolidone, sucrose, starch, isomalt, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin, dextrates, maltodextrinate, and pharmaceutically acceptable salts thereof. In any embodiment, the binder may comprise microcrystalline cellulose. Other acceptable binders include but are not limited to methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), and cellulose derivatives; microcrystalline dextrose; amylose; magnesium silicate; polysaccharide acid (polysaccharide) acids); bentonite; gelatin; vinyl acetate copolymer; sugars such as tragacanth, dextrin, glucose, dextrose, molasses, mannitol; acacia, and gum, larch arabinogalactan, polyethylene glycol, wax, and sodium alginate. The microcrystalline cellulose (MCC) may comprise MCC type PH101, PH102, PH105, PH112, PH113, PH200, PH301, or combinations thereof. The microcrystalline cellulose may comprise a silicified MCC such as Prosolv SMCC® 50, Prosolv SMCC® 90, Prosolv SMCC® HD-90, or combinations thereof.

[0040] In any embodiment of any process of the present disclosure, the pharmaceuticalcomposition can further comprise a starch. The starch can comprise pregelatinized maize starch.

[0041] In any embodiment of any process of the present disclosure, the pharmaceuticalcomposition may further comprise polyvinylpyrrolidone.

[0042] In any embodiment of any process of the present disclosure, the pharmaceuticalcomposition may further comprise magnesium stearate.

[0043] In any embodiment of any process of the present disclosure, the process maycomprise mixing a first portion of dicalcium phosphate dihydrate, and a first portion of pregelatinized starch to form a first base mixture of inactive ingredients; mixing the active pharmaceutical ingredient to the first base mixture of inactive ingredients to form a second base mixture; and mixing a second portion of dicalcium phosphate dihydrate and a second portion of pregelatinized starch to the second base mixture to form the mixture.

[0044] In any embodiment of any process of the present disclosure, the process mayfurther comprise the step of: mixing a first portion of microcrystalline cellulose, a first portion of the dicalcium phosphate dihydrate, and a first portion of pregelatinized starch to form a base mixture of inactive ingredients; adding the active pharmaceutical ingredient to the base mixture of inactive ingredients to form the mixture; blending the mixture with a remaining portion of the microcrystalline cellulose, a remaining portion of the dicalcium phosphate dihydrate, a remaining portion of the pregelatinized starch, and polyvinylpyrrolidone; and blending magnesium stearate into the mixture before the compressing.

[0045] In various embodiments of the present disclosure, the process does not comprise agranulation step. Solid Pharmaceutical Compositions

[0046] Various compositions, for example solid pharmaceutical compositions,comprising a low concentration of active pharmaceutical ingredient(s) that can be prepared from the processes described herein are further provided. For example, the present disclosure provides a pharmaceutical composition comprising: a core comprising: an active pharmaceutical ingredient (API), dicalcium phosphate dihydrate, and at least one excipient; and a polymeric coating comprising a polymeric material coating at least a portion of the core, wherein a coating process is run at an environmental equivalency factor from 1 to 5 and the pharmaceuticalcomposition has a loss on drying less than or equal to 4% (w / w). The coating process of the composition may be run at an environmental equivalency factor of about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5, from about 1 to about 5, from about 1.3 to about 5, from about 1.5 to about 4, from about 2 to about 4, from about 2 to about 3.5, from about 1.4 to about 2.8, from about 2.4 to about 3.8, from about 2.4 to about 2.8, from about 2 to about 3.4, from about 2 to about 3.3, from about 2 to about 3.2, from about 2 to about 3.1, from about 2 to about 3, from about 2 to about 2.9, from about 2 to about 2.8, from about 2 to about 2.7, from about 2 to about 2.6, from about 2 to about 2.5, from about 2 to about 2.4, from about 2 to about 2.3, from about 2 to about 2.2, from about 2 to about 2.1, from about 2.3 to about 2.6, from about 2.1 to about 3.5, from about 2.2 to about 3.5, from about 2.3 to about 3.5, from about 2.4 to about 3.5, from about 2.6 to about 3.5, from about 2.2 to about 3.5, from about 2.7 to about 3.5, from about 2.8 to about 3.5, from about 2.9 to about 3.5, from about 3 to about 3.5, from about 3.1 to about 3.5, from about 3.2 to about 3.5, from about 3.3 to about 3.5, or even from about 3.4 to about 3.5. The loss on drying can be about 4.0% or less, about 3.5% or less, about 3.0% or less, about 2.5% or less, about 2.0% or less, about 1.5% or less, about 1% or less, or about 0.5% or less.

[0047] In some embodiments, the polymeric material may comprise a graft copolymer.The graft copolymer may comprise a polyvinyl alcohol–polyethylene glycol graft copolymer.

[0048] The active pharmaceutical ingredient can comprise a JAK inhibitor, wherein theJAK inhibitor comprises a pyrrolopyrimidine or pyrrolopyridine scaffold. In some embodiments, the JAK inhibitor comprises a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and / or a TYK2 inhibitor. In some embodiments, the active pharmaceutical ingredient can comprise Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, Ilunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and / or Decernotinib, or a pharmaceutically acceptable salt thereof. The active pharmaceutical ingredient can consist or consist essentially of Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, Ilunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and / or Decernotinib, or a pharmaceutically acceptable salt thereof.

[0049] In embodiments compositions described herein may comprise about 15 wt.% orless, about 14.5 wt.% or less, about 14 wt.% or less, about 13.5 wt.% or less, about 13 wt.% or less, about 12.5 wt.% or less, about 12 wt.% or less, about 11.5 wt.% or less, about 11 wt.% orless, about 10.5 wt.% or less, about 10 wt.% or less, about 9.5 wt.% or less, about 9 wt.% or less, about 8.5 wt.% or less, about 8 wt.% or less, about 7.5 wt.% or less, about 7 wt.% or less, about 6.5 wt.% or less, about 6 wt.% or less, about 5.5 wt.% or less, about 5 wt.% or less, about 4.5 wt.% or less, about 4 wt.% or less, about 3.5 wt.% or less, about 3 wt.% or less, about 2.5 wt.% or less, about 2 wt.% or less, about 1.5 wt.% or less, about 1 wt.% or less, or about 0.5 wt.% or less of the active pharmaceutical ingredient. That is, the solid pharmaceutical composition may comprise from about 0.1 wt.% to about 15 wt.%, from about 0.1 wt.% to about 12.5 wt.%, from about 0.1 wt.% to about 10 wt.%, from about 0.1 wt.% to about 7.5 wt.%, from about 0.1 wt.% to about 5 wt.%, from about 0.1 wt.% to about 4.5 wt.%, from about 0.1 wt.% to about 4 wt.%, from about 0.1 wt.% to about 3.5 wt.%, from about 0.1 wt.% to about 3 wt.%, from about 0.1 wt.% to about 2.5 wt.%, from about 0.1 wt.% to about 2 wt.%, from about 0.1 wt.% to about 1.5 wt.%, from about 0.1 wt.% to about 1 wt.%, from about 0.1 wt.% to about 0.5 wt.%, from about 0.5 wt.% to about 3 wt.%, from about 1 wt.% to about 5 wt.%, from about 1.5 wt.% to about 5 wt.%, from about 2 wt.% to about 5 wt.%, from about 2.5 wt.% to about 5 wt.%, from about 3 wt.% to about 5 wt.%, from about 3.5 wt.% to about 5 wt.%, from about 4 wt.% to about 5 wt.%, or even from about 0.5 wt.% to about 5 wt.% of the active pharmaceutical ingredient. In some embodiments, the composition may comprise 0.1 wt.% to 15.0 wt.% of the active pharmaceutical ingredient. The composition may comprise 0.1 wt.%, 0.2 wt.%, 0.3 wt.%, 0.4 wt.%, 0.5 wt.%, 0.6 wt.%, 0.7 wt.%, 0.8 wt.%, 0.9 wt.%, 1.0 wt.%, 1.5 wt.%, 2.0 wt.%, 2.5 wt.%, 3.0 wt.%, 3.5 wt.%, 4.0 wt.%, 4.5 wt.%, 5.0 wt.%, 5.5 wt.%, 6.0 wt.%, 6.5 wt.%, 7.0 wt.%, 7.5 wt.%, 8.0 wt.%, 8.5 wt.%, 9.0 wt.%, 9.5 wt.%, 10.0 wt.%, 10.5 wt.%, 11 wt.%, 11.5 wt.%, 12 wt.%, 12.5 wt.%, 13 wt.%, 13.5 wt.%, 14 wt.%, 14.5 wt.%, or 15 wt.% of the active pharmaceutical ingredient. In some embodiments, the composition may comprise 2.0 wt.% to 3.0 wt.% of the active pharmaceutical ingredient.

[0050] In some embodiments, the composition may comprise from about 1 mg to about150 mg, from about 1 mg to about 125 mg, from about 1 mg to about 100 mg, from about 1 mg to about 95 mg, from about 1 mg to about 90 mg, from about 1 mg to about 85 mg, from about 1 mg to about 80 mg, from about 1 mg to about 75 mg, from about 1 mg to about 70 mg, from about 1 mg to about 65 mg, from about 1 mg to about 60 mg, from about 1 mg to about 55 mg, from about 1 mg to about 50 mg, from about 1 mg to about 45 mg, from about 1 mg to about 40 mg, from about 2 mg to about 40 mg, from about 2 mg to about 35 mg, from about 2 mg to about30 mg, from about 3 mg to about 30 mg, from about 3 mg to about 25 mg, from about 3 mg to about 20 mg, or from about 4 mg to about 20 mg of the active pharmaceutical ingredient. That is, the solid pharmaceutical composition may comprise from about 1 mg to about 150 mg, from about 1 mg to about 125 mg, from about 1 mg to about 100 mg, from about 1 mg to about 95 mg, from about 1 mg to about 90 mg, from about 1 mg to about 85 mg, from about 1 mg to about 80 mg, from about 1 mg to about 75 mg, from about 1 mg to about 70 mg, from about 1 mg to about 65 mg, from about 1 mg to about 60 mg, from about 1 mg to about 55 mg, from about 1 mg to about 50 mg, from about 1 mg to about 45 mg, from about 1 mg to about 40 mg, from about 2 mg to about 40 mg, from about 2 mg to about 35 mg, from about 2 mg to about 30 mg, from about 3 mg to about 30 mg, from about 3 mg to about 25 mg, from about 3 mg to about 20 mg, or even from about 4 mg to about 20 mg of the active pharmaceutical ingredient.

[0051] In some embodiments, the composition may comprise a starch. In someembodiments, the composition may comprise a pregelatinized starch. For example, the starch may comprise pregelatinized maize starch.

[0052] In some embodiments, the composition may further comprise a binder. In someembodiments, the composition may comprise at least one binder selected from the group consisting of microcrystalline cellulose, wood cellulose, ethyl cellulose, carboxymethyl cellulose, lactose, anhydrous lactose, polyvinylpolypyrrolidone, polyvinylpyrrolidone, sucrose, starch, isomalt, pre-gelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin, dextrates, maltodextrinate, and pharmaceutically acceptable salts thereof. In some embodiments, the at least one binder may be microcrystalline cellulose. Other acceptable binders include but are not limited to methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), and cellulose derivatives; microcrystalline dextrose; amylose; magnesium silicate; polysaccharide acid (polysaccharide) acids); bentonite; gelatin; vinyl acetate copolymer; sugars such as tragacanth, dextrin, glucose, dextrose, molasses, mannitol; acacia, and gum, larch arabinogalactan, polyethylene glycol, wax, and sodium alginate. The microcrystalline cellulose (MCC) may comprise MCC type PH101, PH102, PH105, PH112, PH113, PH200, PH301, PH302, or combinations thereof. The micryocrystalline cellulose may comprise a silicified MCCsuch as Prosolv SMCC® 50, Prosolv SMCC® 90, Prosolv SMCC® HD-90, or combinations thereof.

[0053] In some embodiments, the composition may further comprise an excipient. Theexcipient may comprise a starch. For example, the excipient may comprise a pregelatinized starch.

[0054] In some embodiments, the composition may further comprisepolyvinylpyrrolidone.

[0055] In some embodiments, the composition may further comprise magnesiumstearate.

[0056] In some embodiments, the composition may comprise the active pharmaceuticalingredient, the dicalcium phosphate dihydrate, a starch, a synthetic polymer, and a surfactant.

[0057] In some embodiments, the composition may further comprise at least oneadditional ingredient selected from the group consisting of a filler, a disintegrants, a glidant, a lubricant, a complexing agent, a solubilizer, a stabilizer, a preservative, and a surfactant, a polymer, and mixtures thereof. The disintegrant may comprise silicon dioxide.

[0058] In some embodiments, the hardness of the composition may be from about 50 Nto about 250 N, from about 50 N to about 225 N, from about 50 N to about 200 N, from about 50 N to about 175 N, from about 50 N to about 150 N, from about 50 N to about 125 N, or from about 50 N to about 100 N. In other aspects, the hardness of the composition may be more than 50 N, more than 100 N, more than 150 N, more than 200 N, or more than 250 N.

[0059] In some embodiments, the composition may be a tablet.

[0060] In some embodiments, the composition may comprise about 15 wt.% to about 50wt.%, about 25 wt.% to about 40 wt.%, or about 30 wt.% to about 35 wt.% of the dicalcium phosphate dihydrate.

[0061] In some embodiments, the composition may comprise about 30 wt.% to about 70wt.%, about 40 wt.% to about 60 wt.%, or about 45 wt.% to about 55 wt.% of the excipient.

[0062] In some embodiments, the composition may comprise about 1 wt.% to about 25wt.%, about 5 wt.% to about 20 wt.%, or about 10 wt.% to about 15 wt.% of pre-gelatinized starch.

[0063] In some embodiments, the composition may comprise about 0.1 wt.% to about 10wt.%, about 1 wt.% to about 5 wt.%, or about 2 wt.% to about 4 wt.% of polyvinylpyrrolidone.

[0064] In some embodiments, the composition may comprise about 0.1 wt.% to about 3wt.%, about 0.5 wt.% to about 1.5 wt.%, or about 0.8 wt.% to about 1 wt.% of lubricant.

[0065] In some embodiments, the composition may comprise, not including the weight ofthe polymeric coating: 0.5 to 3 wt.% active pharmaceutical ingredient (e.g., Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, Ilunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and / or Decernotinib), 25 to 40 wt.% dicalcium phosphate dihydrate, 10 to 15 wt.% pre-gelatinized starch, 2 to 4 wt.% polyvinylpyrrolidone, 0.5-1.5 wt.% lubricant, and balance filler(s) / other excipient(s). Methods of Treatment

[0066] In another aspect, the present disclosure provides a method of treating adermatological condition comprising administering to an animal (particularly a non-human animal) in need thereof the pharmaceutical composition as disclosed in the paragraphs supra. In some embodiments of the method of treating a dermatological condition, the condition may comprise at least one condition selected from the group consisting of atopic dermatitis, pruritus, skin rash, skin irritation, skin sensitization, allergic reactions, psoriasis, and combinations thereof. The dermatological condition may comprise atopic dermatitis. The dermatological condition may comprise pruritus.

[0067] In some embodiments, the non-human animal may comprise a mammal. In someembodiments, the non-human animal may comprise a dog.

[0068] In some embodiments, the pharmaceutical composition may be administered onceper day. In some embodiments, the pharmaceutical composition may be administered twice per day. In some embodiments, the pharmaceutical composition may be administered once per week. In some embodiments, the pharmaceutical composition may be administered twice per week. In some embodiments, the pharmaceutical composition may be administered once per 12 hours.

[0069] In some embodiments, compositions described herein may be administered at adose of from 0.01 mg of active pharmaceutical ingredient per kg of body weight to 50 mg ofactive pharmaceutical ingredient per kg of body weight, optionally at a dose of from 0.025 mg of active ingredient / kg of body weight to 40 mg of active ingredient / kg of body weight, optionally at a dose of from 0.05 mg of active ingredient / kg of body weight to 30 mg of active ingredient / kg of body weight, optionally at a dose of from 0.1 mg of active ingredient / kg of body weight to 20 mg of active ingredient / kg of body weight, optionally at a dose of from 0.15 mg of active ingredient / kg of body weight to 15 mg of active ingredient / kg of body weight, optionally at a dose of from 0.25 mg of active ingredient / kg of body weight to 10 mg of active ingredient / kg of body weight, optionally at a dose of from 0.5 mg of active ingredient / kg of body weight to 10 mg of active ingredient / kg of body weight, optionally at a dose of from 0.75 mg of active ingredient / kg of body weight to 10 mg of active ingredient / kg of body weight, optionally at a dose of from 1 mg of active ingredient / kg of body weight to 10 mg of active ingredient / kg of body weight, optionally at a dose of from 2 mg of active ingredient / kg of body weight to 7.5 mg of active ingredient / kg of body weight.

[0070] The embodiments of the present invention described below are not intended to beexhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may appreciate and understand the principles and practices of the present invention.

[0071] While illustrative examples of the disclosure have been illustrated and describedin detail in the drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only certain examples have been shown and described and that all changes and modifications that come within the spirit of the claimed invention are desired to be protected. It should be understood that while the use of words such as preferable, preferably, preferred or more preferred utilized in the description above indicates that the feature so described may be more desirable, it nonetheless may not be necessary and examples lacking the same may be contemplated as within the scope of the invention, the scope being defined by the claims that follow. In reading the claims, it is intended that when words such as “a,” “an,” “at least one,” or “at least one portion” are used there is no intention to limit the claim to only one item unless specifically stated to the contrary in the claim. When the language “at least a portion” and / or “a portion” is used the item can include a portion and / or the entire item unless specifically stated to the contrary.

[0072] Unless the context indicates otherwise, it is specifically intended that the variousfeatures of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0073] As used in the description and the appended claims, the singular forms “a,” “an,”and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). The term “about,” as used herein when referring to a measurable value such as an amount of dose, time, temperature, enzymatic activity or other activity and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0074] Following from the above description and invention summaries, it should beapparent to those of ordinary skill in the art that, while the methods and compositions herein described constitute exemplary embodiments of the present invention, the invention contained herein is not limited to this precise embodiment and that changes may be made to such embodiments without departing from the scope of the invention as defined by the claims. Additionally, it is to be understood that the invention is defined by the claims and it is not intended that any limitations or elements describing the exemplary embodiments set forth herein are to be incorporated into the interpretation of any claim element unless such limitation or element is explicitly stated. Likewise, it is to be understood that it is not necessary to meet any or all of the identified advantages or objects of the invention disclosed herein in order to fall within the scope of any claims, since the invention is defined by the claims and since inherent and / or unforeseen advantages of the present invention may exist even though they may not have been explicitly discussed herein.EXAMPLES

[0075] The following examples are for purpose of illustration of the principles andoperation of the processes and compositions of the present disclosure, and should not be construed as limiting the scope of the disclosure. Example 1 – Direct Compression vs. Wet Granulation

[0076] A series of oral tablets containing 7.2 mg of Ilunocitinib were prepared. Directcompression and wet granulation processes were evaluated.

[0077] Direct Compression: Tablets were manufactured by direct compression witheither lactose monohydrate or dibasic calcium phosphate dihydrate as a diluent. The composition of the tablet containing lactose monohydrate and the compositions for the tablet containing dibasic calcium phosphate dihydrate is shown in Table 1.1. Ilunocitinib and all excipients were blended together and compressed into tablets with a nominal target weight of 100 mg and pentagonal shape. Tablets were compressed at different settings. Table 1.1 Ingredients Type N17H083 N17H092 N17I112 N17I113 N17I114 (%w / w) (%w / w) (%w / w) (%w / w) (%w / w) Ilunocitinib API 7.4 7.2 7.2 7.2 7.2 Microcrystalline Binder / 40 – 60 40 – 60 40 – 60 40 – 60 40 – 60 cellulose Filler / DiluentPregelatinized starch Binder 5 – 15 5 – 15 5 – 15 5 – 15 5 – 15Lactose Diluent 15 – 40 - - - - Monohydrate Dibasic calcium Filler / Diluent - 15 – 40 15 – 40 15 – 40 15 – 40 phosphate dihydrate Flavor agent A Flavoring agent 5.0 2.0 - - 5.0 Flavor agent B Flavoring Agent - - - 5.0 - Magnesium stearate Lubricant 0.5 – 3 0.5 – 3 0.5 – 3 0.5 – 3 0.5 – 3 Pigment Coloring agent - 0.2 0.2 0.2 0.2 Total 100.0 100.0 100.0 100.0

[0078] The results of the analytical and physical testing of the tablet batches arepresented in Table 1.2. Friability for the tablet batches which were tested was acceptable with slightly higher values for the tablets with added flavor and the disintegration time of tablets wasmuch longer when flavor (liver or meat) was added to the formulation compared to the non- flavored tablets.Table 1.2. Analytical and Physical Testing Results for Direct Compression TabletsBatch (Sample) Hardness Thickness Disintegration Friability (N) (mm) Time (min:s) (% loss) Content Uniformity N17H083 36 ND 00:37 ND Assay: 103.6% N17H092 45 2.63 00:17 ND ND (2% meat flavor) N17I112 59 2.63 00:10 0.26 Assay mean: 100.0 (no flavor) %AV: 5.1 N17I113 54 2.57 06:45 0.36 Assay mean: 99.2 (5% liver flavor) %AV: 1.3 N17I114 45 2.53 02:47 0.43 Assay mean: 99.9 (5% meat flavor) %AV: 3.5

[0079] Wet-Granulation: Wet granulation was evaluated as an alternativemanufacturing technology to prepare and evaluate a 7.2 mg Ilunocitinib tablet. The composition of the intra-granular phase and the tablet formulation is shown in Table 1.3. Water was used as granulation liquid. Both a red pigment and the liver type dry flavor were added to the external phase.Table 1.3. Granulate / Tablet Based on Wet Granulation Type QTY QTY (%w / w) (mg / tab) Granulate API 30.0 7.20 Diluent 52.32 12.56 Diluent 13.18 3.16 Disintegrant 1.50 0.36 Binder 3.0 0.72 Granulation liquid 24.01NA Total 100.0Tablet API granules 24.0 NA Diluent 40.33 40.33 Binder 9.67 9.67 Diluent 19.80 19.80 Flavoring agent 5.0 5.0 Lubricant 1.0 1.0 Color 0.2 0.2 Total 100.0 100.0

[0080] The blend was compressed into tablets (lot N17H098) with a nominal targetweight of 100 mg and pentagonal shape.

[0081] The results of the analytical and physical testing of the prototype tablet batchbased on wet granulation are presented in Table 1.4. Friability was not tested. Fast disintegration of tablets was observed. Tablet thickness was slightly higher and hardness slightly lower than the one for the flavored direct compression batches based on dibasic calcium phosphate dihydrate). The result of the assay was acceptable.1Water evaporated during drying process.Table 1.4. Analytical and Physical Testing Results of Tablet Based on Wet Granulation Batch (Sample) Hardness Thickness Disintegration Friability (% Assay (N) (mm) time (min:s) loss) N17H098 39 2.71 00:25 ND 98.9 %

[0082] Direct compression was selected as the manufacturing process for further work ofthe Ilunocitinib tablet. This selection was based on the surprising results for tablet properties, especially high content uniformity. Wet granulation was deemed to not be necessary in the further development of the Ilunocitinib tablet. Example 2 – Manufacture of 2.4 mg and 16 mg Tablets for Stability Study

[0083] Material for a stability study (ELA1900399) was prepared with a yellow PVA-PEG coating system. The formulation with composition as shown in Table 2.1 was compressed into tablets of 2.4 mg and 16 mg dose strength, The tablet characteristics for the two dose strengths compressed was as shown in Table 2.2. Table 2.1 Tablet Formulation of the 2.4 mg and 16 mg Ilunocitinib Tablets for Stability StudyIngredient Quantity (% w / w) Target Quantity (% w / w) Tablet core Ilunocitinib 2.4 1 – 5% Microcrystalline cellulose 45 – 50% 40 – 60% Dibasic calcium phosphate 30 – 35% 25 – 40% dihydrate Starch 10 – 15% 5 – 15% Povidone 1 – 3% 1 – 5% Magnesium stearate 0.5 – 1.5% < 3% Coating Yellow PVA-PEG coating 20 – 25% 15 – 30% Purified water 70 – 80% 70 – 85% Removed during coating process Film Coated Tablet Weight: Film Coated Tablet Weight: Film coating with target weight Film coating with target weight gain of 1 – 5% gain of 1 – 55%Table 2.2. Tablet Characteristics of the 2.4 mg and 16 mg Ilunocitinib Tablets for StabilityStudy Dose Strength Tablet Characteristics 2.4 mg Oblong, biconvex, uncoated tablet with score line on both sides 16 mg Oblong, biconvex, uncoated tablet with score line on both sides

[0084] For the 2.4 mg dose strength IPC samples were taken after compression ofapprox.280 (start), 8500 (middle) and 16800 (end) tablets and for the 16 mg dose strength after compression of approx.10 (start), 2500 (middle), and 4900 (end) tablets. The bulk compression resulted in tablets meeting the development limits and with IPC results within a narrow range during the course of the bulk compression. Tablets with fast disintegration and acceptable friability were obtained for both dose strengths.

[0085] Tablets were coated according to the process steps shown in Figure 3 and stabilityof tablets stored in HDPE bottles at 25°C / 60% RH, 30°C / 75% RH, and 40°C / 75% RH was tested. Results of the stability study are presented in Example 4. Table 2.3. Stability Study with (Coated) 2.4 mg and 16 mg Ilunocitinib TabletsDose Strength Tablet Core BatchCoated Tablet Stability Testing Size Batch and Batch (in HDPE Bottles) Size 2.4 mg 16910 tablets B1907-000129 1) Uncoated tablets 8.5 kg 2) Coated tablets 3) Coated tablets with desiccant 16 mg 5370 tablets B1907-000130 4) Coated tablets 8.5 kg Example 3 – 4.8 mg, 6.4 mg, 8.5 mg, and 15 mg Test Formulation Tablets with Yellow Coating

[0086] Ilunocitinib tablets of dose strengths at 4.8 mg, 6.4 mg, 8.5 mg, and 15 mg of theactive substance were prepared with the ingredients as shown in Table 3.1. An aqueous coating process is used to apply the coating to the tablets. Table 3.1. Ilunocitinib Tablets 4.8 mg, 6.4 mg, 8.5 mg, and 15mg Dose Strengths with Yellow CoatingTarget Target Target Target Reference Ingredient Type Quantity (mg Quantity (mg Quantity (mg Quantity (mg to / 4.8 mg / 6.4 mg / 8.5 mg / 15 mg Standard tablet) tablet) tablet) tablet) Tablet core Ilunocitinib Active In-house 4.8 6.4 8.5 15.0 Pharmaceutical Ingredient Microcrystalline Binder / USP / 80 – 120 106.7 – 160 141.7 – 212.5 250 – 375 cellulose / Filler / Diluent Ph.Eur. Cellulose, microcrystalline Dibasic calcium Filler / Diluent USP / 50 – 80 66.7 – 106.7 88.55 – 141.7 156.25 – 250 phosphate Ph.Eur. dihydrate / Calcium hydrogen phosphate dihydrate Pregelatinized Binder USP-NF / 10 – 30 13.3 – 40 17.71 – 53.13 31.25 – 93.75 starch / Starch, Ph.Eur. pregelatinised Povidone Binder USP / 2 – 10 2.67 – 13.34 3.54 – 17.71 6.25 – 31.25 Ph.Eur. Magnesium Lubricant USP-NF / 1 – 6 1.33 – 8 1.77 – 10.626 3.125 – 18.75 stearate Ph.Eur. Weight 200.0 mg 266.7 mg 354.2 mg 625.0 mgCoating Yellow PVA- Coating In-house 6.0 8.0 10.6 18.8 PEG coating Purified water / Processing Aid USP / Removed Removed Removed Removed Water, purified Ph.Eur. during coating during coating during coating during coating process process process process Film Coated Tablet Weight 206.0 mg 274.7 mg 364.8 mg 643.8mg

[0087] For clinical study material supply, one (for 4.8 mg dose strength) to five (for 15mg dose strength) common composition final (lubricated) blend batches were manufactured and used for compression of Test Formulation Tablets. Each blend batch was compressed in its entirety (minus process loss) into one dose strength, and the tablet batch was subsequently coated in its entirety (minus in-process control (IPC) samples and process loss). Tablets were compressed on a pilot scale rotary tablet press and coated in a pilot scale pan coater.

[0088] Blending was performed in a 70 L drum. Pregelatinized starch was used for theIlunocitinib pre-blending process to work with a reduced dilution ratio for Ilunocitinib in the pre- mix compared to using other raw materials and ease handling of raw materials. The Ilunocitinib / pregelatinized starch pre-blend was mixed for 5 minutes. Magnesium stearate was pre-mixed with approximately the same amount of main blend before addition to the 70 L drum for lubrication.

[0089] Compression profiles were obtained for all dose strengths after tablet press set-upand adjustment of parameters to obtain tablets of the target weight (IPC limits were defined for mean and individual hardness). These compression profiles were used to determine the bulk compression settings for each dose strength to obtain tablets of a pre-defined target hardness (which was the main target parameter for bulk compression besides tablet weight). Additional bulk compression target parameters were defined for disintegration time, friability, and thickness (see Table 3.2). All dose strengths were compressed at a tablet press (rotor / turret) and feeder speed, adjusted for each dose strength, to deliver tablets with the target physical attributes. Table 3.2 Hardness Ranges per Dose Strength / Thickness Ranges / Weight Range Attributes Dose strength Target 4.8 mg tablet 200.0 mg (180.0 – 220.0 mg) 6.4 mg tablet 266.7 mg (240 – 293 mg) Tablet Mean Weight 8.5 mg tablet 354.2 mg (319 – 390 mg) 15 mg tablet 625.0 mg (563 – 688 mg) 4.8 mg 90 – 110 N or 55 – 140 N 6.4 mg 115 – 135 N or 75 – 160 N Mean Hardness 8.5 mg 130 – 155 N or 95 – 190 N 15 mg 140 – 175 N or 95 – 230 NDisintegration timeAll dose strengths 1-3 min (< 15min)Friability All dose strengths ≤ 0.2% (< 1%)4.8 mg tablet 3.30 – 3.45 mm or 3.1 – 3.6 mm 6.4 mg tablet 3.85 – 4.0 mm or 3.7 – 4.2 mm Mean Thickness 8.5 mg tablet 4.30 – 4.50 mm or 4.1 – 4.6 mm 15 mg tablet 5.15 – 5.35 mm or 4.8 – 5.5 mm

[0090] Tablets were coated to a target weight gain of 3%. The coating includes thefollowing process steps: loading of the pan coater, pre-warming of the tablet cores, a spraying phase, a drying phase, a cooling phase, and discharge of the pan coater. Fig.3 provides anexemplary flowchart of process steps for the coating process. See example 6 for a detailed description of the different phases of the coating process.

[0091] For all dose strengths and tablet batches, tablet disintegration time was well below15 minutes. For most IPC samples and dose strengths it was within the range of 1 – 3 minutes. The friability result (% loss) was well below 1.0% for all dose strengths. Table 3.3 Hardness and Thickness of the Tablets TabletTablet Batch Number ofTablet Mean Strength Tablets Hardness (N) Thickness CompressedMean BulkBulk (mm)4.8 mg 4 10414292.6 3.26 677785139.7 3.81 6.4 mg 867675128.5 3.86 10 58415151.4 4.20 12 589154.6 4.21 8.5 mg1414 59041150.7 4.26 ( 16 29469170.5 4.93 18 32902161.3 5.01 156 5.02 15 mg20 33236(Min=146, Max= 167) 22 32742149 5.01 24 33501160 5.00

[0092] Tablet content uniformity (see Table 3.4) was determined for all dose strengthsand tablet batches based on the analysis of a composite sample from the bulk compression (10 tablets in total, taken at start / middle / end of bulk compression). Acceptance values (AV) complied for all tablets batches with values well below 15. Table 3.4 Tablet Content UniformityContent in % of Declared Content Tablet Batch 4 6 8 10 12 14 16 18 20 22 24 Dose Strength 4.8 mg 6.4 mg 8.5 mg 15 mgAverage (X) 97.2 96.7 95.4 94.9 96.6 97.9 96.5 98.7 96.1 97.9 95.2Standard Deviation (s) 0.97 1.36 0.90 2.28 0.98 0.89 1.22 1.22 1.36 1.66 2.78%RSD 1.00 1.40 0.95 2.41 1.01 0.91 1.27 1.24 1.41 1.70 2.92 AV 3.6 5.0 5.3 9.1 4.3 2.8 4.9 2.9 5.6 4.6 10.0 Min value 95.7 94.4 93.4 90.0 95.3 96.9 95.0 97.0 94.2 95.6 89.2 Max value 99.4 98.5 96.8 98.2 98.2 99.2 98.3 100.6 98.5 100.5 98.3

[0093] Tablet weight during the coating process, weight gain during the coating process(spraying phase), and the spraying phase duration are summarized for all tablet coating batches in Table 3.5. Table 3.5 Weight Changes of Tablet Batches Dose 4.8 mg 6.4 mg 8.5 mg 15 mg Strength Tablet Batch 4 6 8 10 12 14 16 18 20 22 24Change (% w / w) in tablet1.7 -0.1 0.0 -0.5 -2.1 -0.4 0.1 -2.0 -3.0 -1.8 -3.3weight during pre-warming Duration of spraying phase36 26 37 38 33 38 31 38 36 38 38(min) Weight gain during spraying (%2.89 3.83 4.10 3.20 3.80 2.96 3.10 3.42 3.11 4.01 3.55w / w)

[0094] For most batches, a decrease in tablet weight was observed during the pre-warming phase, while for some batches the tablet weight remained almost unchanged or even increased slightly.

[0095] The weight gain during the spraying phase (based on the tablet weight at the endof the pre-warming phase) was between 2.89% and 4.10%. For subsequent studies, the coating suspension was stirred for some time before use which resulted in a more stable spraying process with better control of tablet weight gain.

[0096] Tablet hardness, thickness and disintegration time were compared for uncoatedand coated tablets to study if the same increase as was observed for the 2.4 mg and 16 mg tablets initial batches manufactured for the stability study (Example 2) was present in the Test Formulation tablets. Tablet thickness increased for all dose strengths and tablet batches and disintegration time increased by approximately 20 – 40 seconds for all dose strengths and tablet batches tested (as data was generated). The observed changes in tablet hardness were less consistent. An increase in tablet hardness after coating was observed for the 4.8 mg tablet and 15 mg tablet batches. Comparable hardness before and after coating was observed for both 6.4 mg tablet batches. A slight decrease in the tablet hardness after coating was observed for all three 8.5 mg tablet batches and 15 mg tablet batches. Release Testing

[0097] The results of the analytical release testing for the Test Formulation batches areshown in Table 3.6. All results were within development specifications for all dose strengths.-9409e.01ltt8.01 9 85.100 o 9 = 3 B 0 B V A -92 09el9130tt .= 1 o 7 V6.0 9 49.A 3 B 0 B g m -90 091el51 9tt5.=610 o 5 V.5B 00 B 9 A 5.3 -98 08 91eltt7.= 0 o 8 V9.5.100 B 9 A 2 3 B -96 08r91e0ts .9= 10il6 V9.9 A 47.3 B B 0 -94 081el9tt3.= 10 88.9.0 o B 9 V A 2 3 B 0 g - 2 9 9el5 m 08 91tt .1=s0 8 V3.8.feh5.10 o 8 9 A 4 3 ocB 0 B 13 - et0r9e=8ga9a.01t 1 9. .s9 7B V P0i9 3l1 90 An B B 0o -i8te9l=74.0a tl13 6t . .9 7 V0 o 5 3u 1 90 A B B 0mrgel=o6.tmt0 2. .F 8 V-4o.5 36 9t 9 A76 B0s1e90r1e0 =T6.B 0t 0 7. .sf 8 Vi5 3lo 9 A Bgnel=it8.t 6 5t . .7 Vs- o 3 3e4g 99 A7 B0T m 190r8.1ee0 =s8.4 B 0t 6 0. .s7aVei3 4l9 AlBe, #Rst5l ≤ es0neehatxt 9 iic l "0.pi≤s mt5t ePmi0emriS0. eyl1 L ou5 Ua C Mq 9 fneroA gb)iy lt6.ttihnt tn r ritna ernh% i3t( ee el lg getm eficr thtV Ktacycb banao nel eo n )a oa a Askiofcsirsbon Wb T TcFtC%a n( sua Alu PIT

[0098] All four dose strengths of the Ilunocitinib tablet (4.8 mg, 6.4 mg, 8.5 mg, and 15mg) were successfully manufactured as Test Formulation tablets. All tablet batches complied with the in-process control (IPC) limits for compression (provisional limits defined for Test Formulation tablets, which were further developed for subsequent studies), and release testing demonstrated all development specifications were met for the coated tablets. Example 4: Hardness of Initial Batches for the Stability Study

[0099] Stability of 2.4 mg and 16 mg tablets (from Example 2) stored in HDPE bottles at25°C / 60% RH, 30°C / 75% RH, and 40°C / 75% RH was tested. Uncoated (without desiccant, results are not shown) and coated tablets (with / without desiccant) in HDPE bottles were compared for the 2.4 mg dose strength. Coated tablets (without desiccant) were tested for the 16 mg dose strength to test for any size / dose strength related effects.

[0100] Appearance of the tablets did not change with storage time. The assay ofIlunocitinib remained stable within the limits of 90.0-110.0% of the declared content throughout the reporting period for all storage conditions tested. No unspecified degradation product was observed at or above the 0.3% VICH reporting limit. The content of total related substances remained below 0.3% throughout the testing period.

[0101] Changes during the storage were however observed for the physical parameterstablet hardness, thickness, weight, and friability and also the water content by Karl-Fischer titration (KF) and the Loss On Drying (LOD).

[0102] Hardness of tablets increased at higher storage temperatures for 2.4 mg coated(30°C / 75% RH and 40°C / 75% RH) (FIG. 1A) and uncoated (40°C / 75% RH) tablets, as well as 16 mg coated tablets (40°C / 75% RH) (FIG.1B). Adding desiccant for storage prevented the increase in hardness for 2.4 mg coated tablets (not tested for 16 mg). At lower temperatures (25°C / 60% RH) hardness remained stable for all tablet strengths and batches tested.

[0103] Thickness of tablets increased at higher storage temperatures (30°C / 75% RH and40°C / 75% RH) for 2.4 mg coated (FIG.1A) and uncoated tablets, as well as 16 mg coated tablets (FIG. 1B). This increase was not observed at lower storage temperatures (25°C / 60% RH) for all tablet strengths and batches tested. Adding desiccant for storage prevented the increase in thickness for 2.4 mg coated tablets (not tested for 16 mg). Notably, 2.4 mg tablets stored withdesiccant displayed lower thickness values compared to tablets stored without desiccant at all timepoints analyzed although the same coated tablet batch was studied.

[0104] For tablets stored without desiccant, water content measured by KF (at roomtemperature) increased with time and storage temperature (FIG.1A-1B). However, water content remained low for tablets stored with desiccant and did not increase over time (not tested for 16 mg). The lower water content for tablets with desiccant at the start of the study was attributed to the use of the desiccant. The start of the stability study was not immediately after manufacturing and surface water in the tablets likely equilibrated to a lower level compared to tablets without desiccant in the HDPE bottles.

[0105] Control of the water content in the commercial Ilunocitinib tablet is ensured bycoating process conditions and in-process controls (LOD) implemented based on the results of subsequent development studies. The addition of desiccant to the packaging was only studied during development studies.

[0106] For tablets stored without desiccant, LOD increased with time and storagetemperature (FIG. 1A-1B). However, LOD remained low for tablets stored with desiccant and only showed a slight increase over time (FIG. 1A, not tested for 16 mg). LOD and water content by Karl Fischer titration (at room temperature) showed similar results. The most pronounced change was observed for tablets stored without desiccant at 40°C / 75% RH, whereas at 30°C / 75% RH there was only a slight increase and at 25 °C / 60% RH it remained stable.

[0107] The tablet weight varied within specification throughout the reporting period forall storage conditions tested. Notably, tablets stored with desiccant displayed lower tablet weight compared to tablets stored without desiccant at all timepoints analyzed although the same batch was used.

[0108] Friability of uncoated 2.4 mg tablets increased with time at all storage conditions.However, friability of coated tablets remained low and well below 1% throughout the reporting period for all storage conditions tested, for both the 2.4 mg and 16 mg dose strength. Conclusions

[0109] The chemical and physical stability of tablets of two dose strengths (2.4 mg and16 mg) packaged in HDPE bottles was tested. In general, no differences were observed between the two dose strengths (2.4 mg and 16 mg). Ilunocitinib tablets remained chemically stable forthe duration of the study at all storage conditions tested and with / without desiccant in the HDPE bottle.

[0110] Tablet physical stability was however found to be affected by the storagecondition (temperature) and configuration (with / without desiccant). Changes in tablet hardness, thickness, friability, water content by KF and the LOD were observed at accelerated conditions (40°C / 75% RH, for 2.4 mg dose strength also at 30°C / 75% RH), but not during storage at lower temperatures (25°C / 60% RH). Stability data also showed that adding desiccant during storage improved physical tablet stability.

[0111] As packaging integrity testing proved that the HDPE bottles were tight and as thetablet weight did not increase over the duration of the study, it was concluded that the additional water / moisture measured by KF / LOD during the study at accelerated conditions was not absorbed from the environment.

[0112] Without being bound by theory, dibasic calcium phosphate dihydrate is thought tolose water of crystallization under certain conditions of temperature and humidity at temperatures well below 100°C. As Ilunocitinib tablets contain 32.4% (w / w) of dibasic calcium phosphate dihydrate, resulting in 6% of crystal water which are present in the formulation, the hypothesis was developed that crystal water which is released during storage would react with povidone and pregelatinized starch water leading to swelling (increase in dimension, e.g. thickness) as well as agglutination / cross-linking with the polymers (and consequently increasing tablet hardness).

[0113] As described above, tablets stored with desiccant had a lower water content by KFand a lower LOD during stability (without any significant increase in LOD or KF during stability), indicating a lower amount of free water in the formulation. These tablets did not show the increase in tablet hardness as was observed for the tablets without desiccant at 40°C / 75% RH (2.4 mg and 16 mg dose strength) and at 30°C / 75% RH for the 2.4 mg dose strength. A partial conversion of the calcium phosphate dihydrate to the anhydrate could be shown for the Ilunocitinib tablets used in the study by XRPD measurements.

[0114] Based on the outcome of the initial stability study, it was concluded that controlof water will likely not be required to maintain the chemical stability of Ilunocitinib tablets but that an initial higher water content in the Ilunocitinib tablet would lead to release of the crystal water and hardness increase at elevated temperature (40°C / 75% RH).Example 5: Hardness of Test Formulation Batches

[0115] Tablet hardness and thickness were studied for tablets manufactured for the use inthe Test Formulation batches (Example 3) and packed into aluminum blisters and HDPE bottles and stored for 24 months at 25°C / 60% RH and 6 months at 40°C / 75% RH. A bracketing approach was chosen for the stability studies, while all four dose strengths were manufactured and packed into both blisters and bottles. The 4.8 mg tablets represent the worst case from a surface-to-volume-ratio perspective.

[0116] Hardness, thickness and water content by KF and LOD for tablets stored at 25°C / 60% RH were measured for 4.8 mg dose strength (FIG.2A) and 15 mg dose strength (FIG. 2B) and for tablets stored at 40°C / 75% RH were measured for 4.8 mg dose strength (FIG.2C) and 15 mg dose strength (FIG.2D).

[0117] The water content (by KF and LOD) at the start of the study was below 4% forboth dose strengths. No significant increase in water content (by KF and LOD) was observed for tablets stored at 25°C / 60% RH and water content stayed for the duration of the study below or at approx.4%. For tablets stored at 40°C / 75% RH however, the water content increased during storage above 4% and reached approx.5.5% at the end of the 6 months storage time. No difference was observed for the two packaging configurations blister vs. bottle.

[0118] For both dose strengths and independent of the packaging configuration, hardnessof tablets stored at 25°C / 60% RH slightly decreased during storage while hardness of tablet stored at 40°C / 75% increased again after an initial drop and reached at the end of the study values which exceeded the initial hardness value. The increase in hardness started once the water content reached approx. 5%.

[0119] For both dose strengths and independent of the packaging configuration, thicknessof tablets stored at 25°C / 60% RH slightly increased during storage. A more pronounced increase in thickness of tablets was observed when stored at 40°C / 75%.

[0120] The results for tablet attributes hardness and thickness and water content duringstability testing for the Test Formulation tablets (Example 3) support a link between storage condition and release of crystal water and subsequent hardness increase during storage. Example 6: Coating Process of Ilunocitinib Tablets

[0121] More detail on the coating process is provided in this Example. An exemplaryprocess for coating tablets according to the present disclosure is shown in FIG.3.

[0122] The four process steps after loading of tablets into, and before discharging tabletsfrom the coater are as follows: Pre-warming of tablet cores

[0123] This phase is intended to pre-warm the tablet cores to a defined temperaturebefore start of spraying the coating suspension. This helps to ensure an efficient and homogeneous coating of the tablet core. The water content of the tablet (originating e.g., from raw materials, influenced by environmental conditions during storage / manufacturing) is reduced during the pre-warming phase. Pre-warming of the tablet cores is driven by the inlet air volume and temperature and controlled by the exhaust air temperature (as indirect measurement of core tablet temperature). Duration of the pre-warming and settings for these process parameter impact on the water content at the end of the phase. Spraying phase

[0124] The spraying phase is the main phase of a coating process. During this, thecoating suspension is added to the tablet cores and the film-coating formed. Process parameters are selected to ensure water added as part of the coating suspension is removed in parallel to the spraying, as indicated by a stable tablet weight by the end of the spraying phase. The Environment Equivalency Factor (EEF) was used to group the coating processes into either“wet”, “intermediate”, or “dry” processes. (A process with an EEF ≤ 2 was categorized as wetprocess. A process with an EEF at approx. 2.5 was categorized as intermediate, an EEF ≥ 2.9was categorized as dry process.) During development, Ilunocitinib tablets were coated at all three process conditions.

[0125] The EEF allows a thermodynamic analysis of the coating process and is definedas the ratio of heat transfer to mass transfer surface areas. The EEF was calculated using the solid contents (%) in the coating suspension, the inlet air flow rate, the inlet air temperature and dewpoint, the suspension spray rate, and the atomization air flow rate (based on the atomization air pressure). The inlet air flow rate and temperature, and spray rate were the key determinants of the EEF which were evaluated during development. The solids content in the coating suspension was kept constant throughout development and the atomization air pressure was also kept constant for most batches (on a given scale). The dewpoint is influenced by the environment.Drying phase

[0126] This phase is intended to start cooling of the tablets at a controlled rate (the inletair temperature will adapt to ensure constant target exhaust air temperature) and ensure the water content of the tablet and the film / coating on the tablet are stabilized. Cooling phase

[0127] This phase is intended to stop heating and let tablets cool down to a lowertemperature before discharging.

[0128] The coating of the initial tablets for the stability study (Example 2) followed theprocess steps outlined in FIG.3 and tablets were coated to a target weight gain of 3%.

[0129] Coating process controls used for coating 2.4 mg tablet batches and 16 mg tabletbatches are shown in Fig.3.

[0130] The weight gain at the end of coating was 3.8% for the 2.4 mg tablet and 3.1% forthe 16 mg tablet. Tablet hardness and thickness increased during the coating process for both dose strengths (see Table 4.1 below), indicating successful formation of an intact film-coat of a certain thickness and mechanical strength. Tablet disintegration time increased during the coating process with yellow PVA-PEG coating (see Table 4.1 below), used during early phases of product development. Dissolution profiles for uncoated and coated tablets were generated at a later stage of the development to demonstrate the observed difference in disintegration time before and after coating does not significantly change the dissolution profiles. Table 4.1 Tablets Processed with Yellow PVA-PEG Coating Strength TabletSample type Weight gain Hardness Thickness Disintegration Batch # (%) during (N) (mm) time (min:sec) coating Uncoated tablet, i average bulk NA 45 2.64 01:49 2.4 mg IPC ii Coated tablet 3.8 57 2.73 02:45 Uncoated tablet, iii average bulk NA 167 5.34 01:03 16 mg IPC iv Coated tablet 3.1 205 5.50 01:37 Example 7: Impact of Coating Process on Water Content

[0131] It was concluded based on the data available from the stability studies that theinitial water content in the tablet after coating is important for the control of hardness andthickness during storage. The water content in the tablet after coating was found to depend on the coating process conditions and how the process impacts the water present in the tablet (originating from API, excipients, environment during dispensing and manufacturing) and the water being sprayed as part of the water-based coating suspension onto the tablets. The impact of the coating process conditions, characterized by the Environmental Equivalency Factor (EEF) (“wet”, “intermediate”, “dry”) on the responses were further evaluated using the data for the studies and batches described above.

[0132] The coating process parameter settings (“recipes”) which were evaluated andcompared are shown in Table 5.1. The five different recipes were evaluated with changes between recipes as described above for Table 5.1. Air flow rate was designated as low (1-249 Nm3 / h), medium (250-449 Nm3 / h), or high (450-749 Nm3 / h). Air temperature was designated as low (1-29 °C), medium (30-50 °C), or high (51-70 °C). Spray rate was designated as low (1-29 g / min), medium (30-59 g / min), or high (60-89 g / min).Table 5.1 Pilot Scale Coating Process Parameters and LevelsProcess Parameters Recipe A Recipe B Recipe C Recipe D Recipe EPre-warming of Tablet Cores – Endpoint Based on Exhaust Air Temperature in °C Inlet air flow rate Medium Medium High High High (Nm3 / h) Inlet air temperature Medium Medium High High High (°C) Exhaust air cut-off Medium Medium High High High temperature (°C) Spraying Phase Endpoint Based on Tablet Mean Weight Gain Inlet air flow rate Medium Medium High High High (Nm3 / h) Inlet air temperature High High High High High (°C) Spray rate (g / min) High High High High High Atomization air 1.2 1.2 1.4 1.2 1.2 pressure (bar) Drying Phase Endpoint Based on Time (Cycle Duration 10 Min) Inlet air flow rate Medium Medium Medium Medium Medium (Nm3 / h) Exhaust air Medium Medium Medium Medium Medium temperature (°C) (setpoint) Cooling Phase Endpoint Based on Time or Exhaust Air Temperature Cut-off Duration: Exhaust air Exhaust air Exhaust air Exhaust air 5min temp.30°C temp.30°C temp.30°C temp.30°C Inlet air flow rate Medium Medium Medium Medium Medium (Nm3 / h)

[0133] The batches evaluated in the coating process development are described in Table5.2.na, etaidemretnisad ezirog etacsaw 5.2 2 gssetna etsn osr ia etgsa. itaec iteteteteyryryrniecei ix udededeootript o r d W W W W D D DtaoorlinC P no C pafmreetmretmrenIntpaCInItam Fp g Eolen e itpiEva cee A A B C B D D EnoaD C R htsise3 - 5 5 w . 9c - 5 4 g r - 5 - - 3sss5 - -sfornith e c b 79 02 70 1 03 94 1 07 61 61 61 50 51 52 2 63 1 4 4 4 030 030 030 4 04ececo 0 ata m90 90 90 0 0 0 00 00 00 8 00 6 0oror4P o B u 1 B 0 10 1 0 0 00 00 0 20 20 2 0 0 2 20 p p eg C N B 0 B 0 0 0 0 B 0 B 0 B 0 D B 0 n ggiB B B Anata .iPo nsstaC d a t e seee3coscrofa M N Nore o,tnd N 7 N N N N N N 0 2 2 N N d c 5 3 9 3 phtnelra 4 61 9 26 9 21 7 0 2 6e1 1 8 19tefotb wtU HraaasaTtsuldaerveH .t H HzorEse iL TlH7 8 4 0 1 2 3r sfee_ _ _2 2 7 3 3 3 4b osbe0 0eb01 1 1 0 0 0 0ca 3 g1 1 10 0 0 0 0 0 0h m 2To set0 0t r00 0 0 0 0 0 04uct0 0 0d pe8a0 0 0 0 0 0 0l- - - - - - - cN 0 0 0ae6tb7 7 9 5 5 5 5y0 0 02r- -hB -as0 0 0 0 0 0 0ata4 4 dc4o 9 9 9 0 0 0 0 Dtg 0 0c 01 1 1 2 2 2 2 w nasn 0 0 0nao B B B B B B BiB 2t2 2 2 U dda B B B ≤eoerzF)C )i urnrsE2 3 IIoIoVe oIlafy g g giEtlege eylsltt siy tssn n nai i s ia saisld pepscltidnes elmt e t te atiuea c a aueucS batbhcsmmcatTco o oa anshoItarSmto sr rtt oxsxrteC C CiaosPo PaP nlbiEE( (w F dwPrsas9.2.hh etg g g g gc2g5 tgesm m m m mome≥nr lelo e p64 8 8 8 8. . . . .bFb Drat12 4 4 4 4a EA T S 2 T Eetaetaeti iaietaetdiatetetetetedede ediedeW W W W Wmrtmermermrmntentent re IIntI InIA E E 95-96 -98 -90 -92 -94 -88 -89 -80 -67 -68 fo081 081 091 091 091 070 070 08 04 04 1910 910 910 910 90 00 00 000 000 000 4 0 00 0 0 1 0 0 2 0 0 0 2 0 0 2 B B 0 2 B 0 2 B B 0 e B 0 B 0 B 0 B 0 B 0gaP N N N N N N N N N N 0 1 6 9 0 5 3 1 6 971 61 51 41 61 01 61 22 51 51 68 8 0 2 4 8 9 1 81 91 91 9 7 0 0 7 0 0 0 8 74 80 0 0 1 0 0 0 40000 0 0 0 0 0 0 00 0- -0 00 0 0 0 0 0- -0 00 9 9 9 9 -9 - 0 0 8 -8 -9 0 0 8 -00 6 -0 9 0 0 0 609 9 9 0 0 0 0 01 1 1 1 1 2 2 2 2 2 B B B B B B B B B B )n I3oI VI Ig giteslttn ni isa slpssselet tua ae ebc cTmo oaamtro oxr rC Co P PE(F g g g m m m 5 5 51 1 1

[0134] Dedicated blend batches (studies “Coating Process I”, “Coating Process II”,“Coating Process III”) were manufactured for the purpose of studying the coating process in addition to coated tablets which were available from other studies (e.g. initial batches for the stability study (Example 2), Test Formulation tablets (Example 3), and Coating Process IV) and included in the evaluation of coating process parameters. The blending process used for the manufacturing of these final (lubricated) blends and additional use of uncoated tablets compressed as part of these sub-studies are shown in Table 5.3. Table 5.3 Blending Process for Additional Pilot Scale Coating Batches Evaluated for Coating Process Development (Sub-)Study Blending Process Variation Coated Tablet BatchCoating Process I blending 30 minutes at 17 rpm,4.8 mg B2004-000010_LH followed by lubrication for 3 minutes / TH / HH at 17 rpm, magnesium stearate was added through 0.50 mm sieve as 1:1 pre-mix in bag with main blend Coating Process blending 30 minutes at 18 rpm, 4.8 mg B2005-000030 II followed by lubrication for 3 minutes 4.8 mg B2005-000031 at 18 rpm, magnesium stearate was 4.8 mg B2005-000032 added through 0.50 mm sieve as 1:1 pre-mix in bag with main blend Coating Process blending 30 minutes at 20 rpm, 15 mg B2008-000078 III followed by lubrication for 5 minutes 15 mg B2008-000079 at 20 rpm, magnesium stearate was 15 mg B2008-000080 added through 0.50 mm sieve as 1:1 Coating Process pre-mix in bag with main blend 4.8 mg B2006-000043 IV 15 mg B2006-000047 15 mg B2006-000048

[0135] These batches with different coating recipes were then compared. First, tabletweight after the pre-warming phase of the coating process was compared to the uncoated tablet weight. Weight loss during the pre-warming phase is shown together with the calculated surface water of the same tablet batch (as data was available) in Table 5.4.

[0136] The observed weight loss during the pre-warming phase was in general lower fortablet batches coated at process conditions per recipe A and B compared to the tablet batches coated using recipes C, D, and E. The inlet air temperature for recipes A and B was set to medium inlet air temperature (compared to high inlet air temperature for C, D, and E) and the exhaust air temperature cut-off to medium temperature (compared to high temperature for C, D, and E). The exhaust air temperature is considered an indirect measurement of tablet core temperature at the end of the pre-warming phase. The higher cut-off temperature for recipes C, D, and E led in general to higher observed water loss and lower surface water content at the end of the pre-warming phase.Table 5.4 Weight Loss During Pre-Warming and Surface Water Content Grouped by Coating Recipe Study Coating Batch Coating Weight Loss During Surface Water of Number Recipe Used Pre-warming in % Coated Tablet in % Initial Batches B1907-000129 -0.48% NA for Stability Study B1907-000130 -0.29% NA (Example 2) B1909-000174 NA 3.28 Recipe A Test B1909-000186 0.02%173.25 Formulation B1909-000188 -0.32% 3.43 Tablets B1909-000190 -0.46% NA (Example 3) B1909-000192 -0.29% NA B1909-000194 -0.53% NA B000041653 -0.75% 2.70 Coating Recipe B Process I B000041654 -0.71% 2.65 B000041655 Recipe C -1.06% 2.10 B2005-000030 -1.77% NA Coating Process II B2005-000032 Recipe D -1.27% NA D268423 -1.40% NA B2006-000043 -1.37% 2.43 Coating Process IV B2006-000047 -1.22% 2.47 B2006-000048 -0.93% NA Recipe E B2008-000078 NA NA Coating Process III B2008-000079 -1.02% NA B2008-000080 -0.63% NA

[0137] The EEF for the five recipes was then calculated for the parameter settings duringthe spraying phase of the coating process to characterize the coating process. Based on the target values for the process parameters (see Table 5.1) recipe A and B lead to an EEF of approx.1.9 (wet condition), recipe C leads to an EEF of approx. 3.4 (dry condition) and recipe E leads to an EEF of 2.6 (intermediate conditions). For Batch B000041654 (run according to recipe B), a defect in the flow meter led to a lower than targeted spray rate of approx.40 g / min (instead of 65 g / min), leading to an EEF of approx. 3.1 (dry conditions).

[0138] Variability in the resulting surface water content was observed, independent of thecoating process conditions. The coating process for the Test Formulation tablets (Example 3) (recipe A / wet conditions) led to a higher surface water content (> 3.2%) compared to the coating process for the Coating Process I study (two batches recipe B, one wet and one dryconditions, one batch recipe C dry conditions) and the Coating Process IV study (recipe E dry process conditions, < 2.7%).

[0139] Coating Process I study batch B000041653 (wet conditions) and batchB000041654 (dry conditions) resulted in a comparable water content of 2.7% and 2.65% respectively. Coating Process I study batches B000041654 and B000041655 (both dry conditions) resulted in a water content of 2.65% and 2.1% respectively. Batches from the Coating Process IV study (intermediate conditions) resulted in a water content of 2.43% and 2.47%, respectively.

[0140] These observations lead to the conclusion that the coating process conditionsduring the spraying phase (wet, intermediate, or dry conditions, according to EEF) do not significantly impact the estimated surface water content in %, which aligns with the observations that the coating process conditions do not impact physical tablet properties after coating and during stability. Impact of pre-warming phase on estimated surface water content

[0141] Two clusters were identified according to pre-warming phase recipes: recipes Aand B (low air flow volume, low air temperature) and recipes C, D and E (high air flow volume, high air temperature).

[0142] Batches produced with recipes A and B (Test Formulation tablets from Example 3and first part of Coating Process I) lead to surface water content above 2.5% while batches produced with recipes C and E lead to surface water content below 2.5%.

[0143] This correlation is strong within Coating Process I study, with batchesB000041653 and B000041654 (recipe B) having surface water content of 2.65% and 2.7% and batch B000041655 having surface water content of 2.1%.

[0144] These observations lead to the conclusion that the pre-warming phase impactssurface water content after coating, which is an important parameter for tablet attribute stability over time.

[0145] The results indicated that the main driver of surface water content in the tablets isthe pre-warming phase during the coating step. Some remaining variability could be attributed to the surface water content of the blend, or the tablets at start of the pre-warming phase.Overall Conclusions on Coating Process Development

[0146] Ilunocitinib tablet is a film coated immediate release tablet. The coating is non-functional and delivers a yellow color to the tablets. For the following Ilunocitinib tablet Critical Quality Attributes (CQAs, appearance, identity, potency, purity, content uniformity and release rate) a potential impact of the coating process was identified: appearance (coating process delivers color to tablet), potency (coating process could impact tablet hardness and thus also divisibility), and release rate (coating process could impact tablet attributes such as hardness, which impact on dissolution rate).

[0147] During the development of the coating process, intermediate material attributes(uncoated tablet hardness, solid fraction) and process steps (pre-warming phase, spraying phase) were varied and the impact on coated tablet attributes after coating and during stability evaluated. Impact of packaging type

[0148] Batches were packed either in aluminum blister or in HDPE bottles with plastic oraluminum caps. No difference was observed between the different packaging types during the five stability studies described above. Impact of uncoated tablet hardness and solid fraction

[0149] Uncoated tablet hardness and solid fraction did not impact coated tablet attributesduring stability. In addition, no correlation was observed between initial tablet hardness or solid fraction and the hardness increase for the coated tablets compared to uncoated tablets. Impact of coated tablet surface water content on tablet attributes during storage

[0150] Surface water content (measured by LOD and KF at room temperature) above acertain threshold was found to trigger tablet hardness increase at elevated temperatures. Using the data from stability studies, the threshold was determined to be between 4% and 5% surface water content.

[0151] An increase in water content was observed for: 1) tablets stored at 40°C / 75% RH(crystal water from dibasic calcium phosphate dihydrate can be released at elevated temperature (already at 40°C) and this release is promoted by presence of surface water, and 2) tablets stored at 30°C / 75% RH for which the initial water content was already high (> 4%). No increase in water content was observed for any of the tablets stored at 25°C / 60% RH.

[0152] Limiting the surface water content to below 4 – 5% during storage will limitchanges in tablet properties. In order to accomplish this, targeting a low initial water content after coating (e.g., below 3.0%) is recommended to avoid a water increase at 30°C / 75% RH and delay the water increase at 40°C / 75% RH. Impact of process parameters during spraying phase (EEF)

[0153] The coating process conditions during the spraying phase (wet, intermediate, ordry conditions, according to EEF) do not significantly impact changes in tablet attributes (hardness, thickness) after coating and during stability, nor do they significantly impact the estimated surface water content after coating. Therefore, no impact on potency or release rate is expected. However, even if all conditions fulfill the appearance specification, a wet process is not desirable as some tiny holes in the tablet / coating were observed. Therefore, the recommendation is to run the coating process at conditions resulting in an intermediate EEF. Impact of process parameters during pre-warming phase

[0154] Two sets of parameters for the pre-warming phase were tested duringdevelopment leading to tablet core temperatures at the end of the pre-warming phase of medium or high temperature (indirectly measured by exhaust air temperature). This difference in tablet core temperature at the end of the pre-warming phase led to pronounced differences in weight loss during the pre-warming (related to water loss), and also to differences in surface water content of the coated tablet.

[0155] Surface water content after coating was shown to be an important determinant fortablet attribute stability over time. Therefore, it is recommended to run the pre-warming of tablet cores at process conditions allowing for stronger drying of the tablet cores (at pilot scale e.g. high inlet air temperature, high exhaust air temperature for cut-off). Example 8: Blend uniformity measurement

[0156] Premixes blend uniformity is measured using near infrared spectroscopy (NIRS),according to United States Pharmacopia / Ph.Eur. standard methodology. Each sample is analyzed in triplicate, and the average of the three measurements is reported as the result. Blend uniformity (BU) of the pre-lubrication mix was tested with high performance liquid chromatography (HPLC) methods. BU is tested after 10 minutes, 20 minutes, and 30 minutes ofblending, with results in Table 6.1 below. The processes for producing Main Blend Batches #1 and #2 are shown in FIG. 4. Table 6.1Main Blend Batch #1 #2Blending time 10 min 20 min 30 min 10 min 20 min 30 minAssay average 99.5 101.2 100.2 97.4 98.1 97.8Min 96.4 99.5 98.0 95.9 96.6 96.6Max 101.0 103.3 103.4 98.8 99.4 99.8Standard deviation 1.33 1.24 1.51 0.89 1.00 1.13Standard relative1.34 1.23 1.51 0.91 1.02 1.16deviation (Srel) USP Acceptance3.2 3.0 3.6 3.2 2.8 3.4Value (AV) value

[0157] Comparable BU results were obtained for both blending process and both theaddition of API:pregelatinized starch 1:1 pre-mix or as pre-blend with the full quantity of pregelatinized starch, wherein the API may be Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, Ilunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and / or Decernotinib.

[0158] The two evaluated main-blending processes lead to good blend uniformity resultsindependently of pre-blending method and main blending duration. However, it could not be completely ruled out that the longer blending time led to the low / high result (which then might indicate beginning de-mixing). Further work was continued with the addition of Ilunocitinib as API:pregelatinized starch 1:1 pre-mix.

[0159] While embodiments have been disclosed hereinabove, the present invention is notlimited to the disclosed embodiments. Instead, this application is intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A solid pharmaceutical composition, comprising: an active pharmaceutical ingredient; and at least one excipient, wherein the solid pharmaceutical composition has a tensile strength from about 0.5 Mpa to about 5 Mpa when compressing a mixture comprising the active pharmaceutical ingredient and the at least one excipient with a compression pressure from about 50 Mpa to about 450 Mpa.

2. The solid pharmaceutical composition of claim 1, wherein the solid pharmaceutical composition has a tensile strength from 1 Mpa to 3 Mpa when compressing the mixture with a compression pressure from 150 Mpa to 300 Mpa, optionally 150 Mpa to 250 Mpa.

3. The solid pharmaceutical composition of claim 1 or 2. wherein the mixture has a blend uniformity is from 75% to 125% of an average content of the active pharmaceutical ingredient.

4. The solid pharmaceutical composition of any one of claims 1 to 3, wherein the solid pharmaceutical composition further comprises dicalcium phosphate dihydrate.

5. The solid pharmaceutical composition of any one of claims 1 to 4, further comprising a polymeric coating.

6. The solid pharmaceutical composition of claim 5, wherein a coating process is run at an environmental equivalency factor from 1 to 5, optionally from 1.3 to 5, optionally from 1.5 to 4, optionally from 2 to 4, optionally from 2 to 3.5, optionally from 1.4 to 2.8, optionally from 2.4 to 3.8, optionally from 2.4 to 2.8, optionally from 2.3 to 2.6, optionally from 2 to 2.

2.

7. The solid pharmaceutical composition of claim 5 or 6, wherein the polymeric coating comprises a graft copolymer.

8. The solid pharmaceutical composition of claim 7, wherein the graft copolymer comprises a polyvinyl alcohol – polyethylene glycol graft copolymer.

9. The solid pharmaceutical composition of any one of claims 1 to 8, wherein the active pharmaceutical ingredient comprises a Janus Kinase (JAK) inhibitor.

10. The solid pharmaceutical composition of claim 9, wherein the JAK inhibitor comprises a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and / or a TYK2 inhibitor.

11. The solid pharmaceutical composition of claim 9 or 10, wherein the JAK inhibitor comprises a pyrrolopyrimidine or pyrrolopyridine scaffold.

12. The solid pharmaceutical composition of any one of claims 1 to 11, wherein the active pharmaceutical ingredient comprises Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, Ilunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and / or Decernotinib, or a pharmaceutically acceptable salt thereof.

13. The solid pharmaceutical composition of any one of claims 1 to 12, wherein the active pharmaceutical ingredient consists essentially of Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, Ilunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and / or Decernotinib, or a pharmaceutically acceptable salt thereof.

14. The solid pharmaceutical composition of any one of claims 1 to 13, wherein the active pharmaceutical ingredient consists of Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, Ilunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and / or Decernotinib, or a pharmaceutically acceptable salt thereof.

15. The solid pharmaceutical composition of any one of claims 1 to 14, wherein the solid pharmaceutical composition comprises about 15 wt.% or less, about 14.5 wt.% or less, about 14 wt.% or less, about 13.5 wt.% or less, about 13 wt.% or less, about 12.5 wt.% or less, about 12 wt.% or less, about 11.5 wt.% or less, about 11 wt.% or less, about 10.5 wt.% or less, about 10 wt.% or less, about 9.5 wt.% or less, about 9 wt.% or less, about 8.5 wt.% or less, about 8 wt.% or less, about 7.5 wt.% or less, about 7 wt.% or less, about 6.5 wt.% or less, about 6 wt.% or less,about 5.5 wt.% or less, about 5 wt.% or less, about 4.5 wt.% or less, about 4 wt.% or less, about 3.5 wt.% or less, about 3 wt.% or less, about 2.5 wt.% or less, about 2 wt.% or less, about 1.5 wt.% or less, about 1 wt.% or less, or about 0.5 wt.% or less of the active pharmaceutical ingredient.

16. The solid pharmaceutical composition of any one of claims 1 to 15, wherein the solid pharmaceutical composition comprises from about 0.1 wt.% to about 15 wt.%, from about 0.1 wt.% to about 12.5 wt.%, from about 0.1 wt.% to about 10 wt.%, from about 0.1 wt.% to about 7.5 wt.%, from about 0.1 wt.% to about 5 wt.%, from about 0.1 wt.% to about 3 wt.%, from about 0.5 wt.% to about 5 wt.%, from about 0.5 wt.% to about 3 wt.%, from about 1 wt.% to about 5 wt.%, or from about 1 wt.% to about 3 wt.% of the active pharmaceutical ingredient.

17. The solid pharmaceutical composition of any one of claims 1 to 16, wherein the solid pharmaceutical composition comprises from about 1 mg to about 150 mg, from about 1 mg to about 125 mg, from about 1 mg to about 100 mg, from about 1 mg to about 95 mg, from about 1 mg to about 90 mg, from about 1 mg to about 85 mg, from about 1 mg to about 80 mg, from about 1 mg to about 75 mg, from about 1 mg to about 70 mg, from about 1 mg to about 65 mg, from about 1 mg to about 60 mg, from about 1 mg to about 55 mg, from about 1 mg to about 50 mg, from about 1 mg to about 45 mg, from about 1 mg to about 40 mg, from about 2 mg to about 40 mg, from about 2 mg to about 35 mg, from about 2 mg to about 30 mg, from about 3 mg to about 30 mg, from about 3 mg to about 25 mg, from about 3 mg to about 20 mg, or from about 4 mg to about 20 mg of the active pharmaceutical ingredient.

18. The solid pharmaceutical composition of any one of claims 1 to 17, wherein the excipient comprises a starch.

19. The solid pharmaceutical composition of any one of claims 1 to 18, wherein the excipient comprises a pregelatinized starch.

20. The solid pharmaceutical composition of any one of claims 1 to 19, wherein the solid pharmaceutical composition further comprises a binder.

21. The solid pharmaceutical composition of claim 20, wherein the binder comprises at least one member selected from microcrystalline cellulose, wood cellulose, ethyl cellulose, carboxymethyl cellulose, lactose, anhydrous lactose, polyvinylpolypyrrolidone, polyvinylpyrrolidone, sucrose, starch, isomalt, pre-gelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium sulfate, dextrin, dextrates, maltodextrinate, and pharmaceutically acceptable salts thereof.

22. The solid pharmaceutical composition of claim 20 or 21, wherein the binder comprises microcrystalline cellulose and / or polyvinylpyrrolidone.

23. The solid pharmaceutical composition of any one of claims 1 to 22, wherein the solid pharmaceutical composition further comprises magnesium stearate.

24. The solid pharmaceutical composition of any one of claims 1 to 23, wherein the solid pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a filler, a disintegrants, a glidant, a lubricant, a complexing agent, a solubilizer, a stabilizer, a preservative, and a surfactant, a polymer, and mixtures thereof.

25. The solid pharmaceutical composition of any one of claims 1 to 24, wherein the solid pharmaceutical composition has a hardness of from about 50 N to about 250 N, from about 50 N to about 225 N, from about 50 N to about 200 N, from about 50 N to about 175 N, from about 50 N to about 150 N, from about 50 N to about 125 N, or from about 50 N to about 100 N.

26. A pharmaceutical composition comprising: a core comprising: an active pharmaceutical ingredient, dicalcium phosphate dihydrate, and at least one excipient; and optionally a polymeric coating comprising a polymeric material coating at least a portion of the core,wherein a coating process is run at an environmental equivalency factor from 1 to 5 and the pharmaceutical composition has a loss on drying less than or equal to 4% (w / w).

27. The pharmaceutical composition of claim 26, wherein the active pharmaceutical ingredient comprises a JAK inhibitor, wherein the JAK inhibitor comprises a pyrrolopyrimidine or pyrrolopyridine scaffold.

28. The pharmaceutical composition of claim 27, wherein the JAK inhibitor comprises a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and / or a TYK2 inhibitor.

29. The pharmaceutical composition of any one of claims 26 to 28, wherein the active pharmaceutical ingredient comprises Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, Ilunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and / or Decernotinib, or a pharmaceutically acceptable salt thereof.

30. The pharmaceutical composition of any one of claims 26 to 29, wherein the active pharmaceutical ingredient consists or consists essentially of Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, Ilunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and / or Decernotinib, or a pharmaceutically acceptable salt thereof.

31. The pharmaceutical composition of any one of claims 26 to 30, wherein the pharmaceutical composition comprises about 15 wt.% or less, about 14.5 wt.% or less, about 14 wt.% or less, about 13.5 wt.% or less, about 13 wt.% or less, about 12.5 wt.% or less, about 12 wt.% or less, about 11.5 wt.% or less, about 11 wt.% or less, about 10.5 wt.% or less, about 10 wt.% or less, about 9.5 wt.% or less, about 9 wt.% or less, about 8.5 wt.% or less, about 8 wt.% or less, about 7.5 wt.% or less, about 7 wt.% or less, about 6.5 wt.% or less, about 6 wt.% or less, about 5.5 wt.% or less, about 5 wt.% or less, about 4.5 wt.% or less, about 4 wt.% or less, about 3.5 wt.% or less, about 3 wt.% or less, about 2.5 wt.% or less, about 2 wt.% or less, about 1.5 wt.% or less, about 1 wt.% or less, or about 0.5 wt.% or less of the active pharmaceutical ingredient.

32. The pharmaceutical composition of any one of claims 26 to 31, wherein the pharmaceutical composition comprises from about 0.1 wt.% to about 15 wt.%, from about 0.1 wt.% to about 12.5 wt.%, from about 0.1 wt.% to about 10 wt.%, from about 0.1 wt.% to about 7.5 wt.%, from about 0.1 wt.% to about 5 wt.%, from about 0.1 wt.% to about 3 wt.%, from about 0.5 wt.% to about 5 wt.%, from about 0.5 wt.% to about 3 wt.%, from about 1 wt.% to about 5 wt.%, or from about 1 wt.% to about 3 wt.% of the active pharmaceutical ingredient.

33. The pharmaceutical composition of any one of claims 26 to 32, wherein the pharmaceutical composition comprises from about 1 mg to about 150 mg, from about 1 mg to about 125 mg, from about 1 mg to about 100 mg, from about 1 mg to about 95 mg, from about 1 mg to about 90 mg, from about 1 mg to about 85 mg, from about 1 mg to about 80 mg, from about 1 mg to about 75 mg, from about 1 mg to about 70 mg, from about 1 mg to about 65 mg, from about 1 mg to about 60 mg, from about 1 mg to about 55 mg, from about 1 mg to about 50 mg, from about 1 mg to about 45 mg, from about 1 mg to about 40 mg, from about 2 mg to about 40 mg, from about 2 mg to about 35 mg, from about 2 mg to about 30 mg, from about 3 mg to about 30 mg, from about 3 mg to about 25 mg, from about 3 mg to about 20 mg, or from about 4 mg to about 20 mg of the active pharmaceutical ingredient.

34. The pharmaceutical composition of any one of claims 26 to 33, wherein the pharmaceutical composition further comprises a binder.

35. The pharmaceutical composition of any one of claims 26 to 34, wherein the core comprises at least one binder selected from the group consisting of microcrystalline cellulose, wood cellulose, ethyl cellulose, carboxymethyl cellulose, lactose, anhydrous lactose, polyvinylpolypyrrolidone, polyvinylpyrrolidone, sucrose, starch, isomalt, pre-gelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin, dextrates, maltodextrinate, and pharmaceutically acceptable salts thereof.

36. The pharmaceutical composition of claim 35, wherein the at least one binder is microcrystalline cellulose.

37. The pharmaceutical composition of any one of claims 26 to 36, wherein the excipient comprises a starch.

38. The pharmaceutical composition of any one of claims 26 to 37, wherein the excipient comprises a pregelatinized starch.

39. The pharmaceutical composition of any one of claims 26 to 38, wherein the pharmaceutical composition comprises polyvinylpyrrolidone.

40. The pharmaceutical composition of any one of claims 26 to 39, wherein the pharmaceutical composition further comprises magnesium stearate.

41. The pharmaceutical composition of any one of claims 26 to 40, wherein the pharmaceutical composition comprises the active pharmaceutical ingredient, the dicalcium phosphate dihydrate, a starch, a synthetic polymer, and a surfactant.

42. The pharmaceutical composition of any one of claims 26 to 41, wherein the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a filler, a disintegrants, a glidant, a lubricant, a complexing agent, a solubilizer, a stabilizer, a preservative, and a surfactant, a polymer, and mixtures thereof.

43. The pharmaceutical composition of any one of claims 26 to 42, wherein the polymeric material comprises a graft copolymer.

44. The pharmaceutical composition of claim 43, wherein the graft copolymer comprises a polyvinyl alcohol – polyethylene glycol graft copolymer.

45. The pharmaceutical composition of any one of claims 26 to 44, wherein a hardness of the pharmaceutical composition is from about 50 N to about 250 N, from about 50 N to about 225 N,from about 50 N to about 200 N, from about 50 N to about 175 N, from about 50 N to about 150 N, from about 50 N to about 125 N, or from about 50 N to about 100 N.

46. The pharmaceutical composition of any one of claims 26 to 45, wherein the pharmaceutical composition is a tablet.

47. The pharmaceutical composition of any one of claims 26 to 46 comprising about 15 wt.% to about 50 wt.%, about 25 wt.% to about 40 wt.%, or about 30 wt.% to about 35 wt.% of the dicalcium phosphate dihydrate.

48. The pharmaceutical composition of any one of claims 26 to 47 comprising about 30 wt.% to about 70 wt.%, about 40 wt.% to about 60 wt.%, or about 45 wt.% to about 55 wt.% of the excipient.

49. The pharmaceutical composition of any one of claims 26 to 48 comprising about 1 wt.% to about 25 wt.%, about 5 wt.% to about 20 wt.%, or about 10 wt.% to about 15 wt.% of pre- gelatinized starch.

50. The pharmaceutical composition of any one of claims 26 to 49 comprising about 0.1 wt.% to about 10 wt.%, about 1 wt.% to about 5 wt.%, or about 2 wt.% to about 4 wt.% of polyvinylpyrrolidone.

51. The pharmaceutical composition of any one of claims 26 to 50 comprising about 0.1 wt.% to about 3 wt.%, about 0.5 wt.% to about 1.5 wt.%, or about 0.8 wt.% to about 1 wt.% of lubricant.

52. The pharmaceutical composition of any one of claims 26 to 51, wherein the composition comprises: 0.5 to 3 wt.% active pharmaceutical ingredient (e.g., Ruxolitinib, Tofacitinib, Oclacitinib, Baricitinib, Ilunocitinib, Peficitinib, Delgocitinib, Abrocitinib, Ritlecitinib, and / or Decernotinib), 25 to 40 wt.% dicalcium phosphate dihydrate,10 to 15 wt.% pre-gelatinized starch, 2 to 4 wt.% polyvinylpyrrolidone, and 0.5 to 1.5 wt.% lubricant.

53. A method of treating a dermatological condition comprising administering to a non-human mammal in need thereof the pharmaceutical composition of any one of claims 1 to 52.

54. The method of claim 53, wherein the dermatological condition comprises at least one condition selected from the group consisting of atopic dermatitis, pruritus, skin rash, skin irritation, skin sensitization, allergic reactions, psoriasis, and combinations thereof.

55. The method of claim 53 or 54, wherein the dermatological condition comprises atopic dermatitis.

56. The method of claim 53 or 54, wherein the dermatological condition comprises pruritus.

57. The method of any one of claims 53 to 56, wherein the non-human animal comprises a dog.

58. The method of any one of claims 53 to 57, wherein the pharmaceutical composition is administered once per day.

59. The method of any one of claims 53 to 58, wherein the pharmaceutical composition is administered at a dose of 0.01 mg of active ingredient / kg of body weight to 50 mg of active ingredient / kg of body weight, optionally at a dose of 0.025 mg of active ingredient / kg of body weight to 40 mg of active ingredient / kg of body weight, optionally at a dose of 0.05 mg of active ingredient / kg of body weight to 30 mg of active ingredient / kg of body weight, optionally at a dose of 0.1 mg of active ingredient / kg of body weight to 20 mg of active ingredient / kg of body weight, optionally at a dose of 0.15 mg of active ingredient / kg of body weight to 15 mg of active ingredient / kg of body weight, optionally at a dose of 0.25 mg of active ingredient / kg of body weight to 10 mg of active ingredient / kg of body weight, optionally at a dose of 0.5 mg of active ingredient / kg of body weight to 10 mg of active ingredient / kg of body weight, optionally at a doseof 0.75 mg of active ingredient / kg of body weight to 10 mg of active ingredient / kg of body weight, optionally at a dose of 1 mg of active ingredient / kg of body weight to 10 mg of active ingredient / kg of body weight, optionally at a dose of 2 mg of active ingredient / kg of body weight to 7.5 mg of active ingredient / kg of body weight.

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