Formulations, methods, kits, and dosage forms for treating atopic dermatitis and for improved stability of an active pharmaceutical ingredient

A kit comprising one or more dosage forms for treating one or more diseases characterized by the dysregulation of the Syk/JAK pathway and instructions for administering the dosage forms to a subject, wherein the dosage forms comprise granules and extragranular components compressed into a tablet, and wherein:

• the micronized granules comprise:
• micronized active ingredient;
• one or more granulation binders;
• one or more fillers;
• one or more disintegrants;
• and one or more antioxidants;
• the extragranular components comprise one or more tableting fillers, one or more disintegrants, one or more lubricants, and optionally one or more surfactants;
• the active ingredient is a compound of Formula (I) or a pharmaceutically acceptable salt, enantiomer or prodrug thereof,
• wherein R1 is a 6-membered ring of Formula (II):
• wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or (C1 to C6) alkyl CN;
• and
• wherein R2 is a benzene ring of Formula (III);
• wherein R4 is a 6-membered ring of Formula (IV):
• wherein R5 is N or CH and R6 is a hydroxyl group, methyl group, or ethyl group, and wherein the formulation has a total API degradation impurity level not above about 0.6% of the total active ingredient amount after storage at 1 week at 40° C./75% RH in an open container.

A dosage form for treating one or more diseases characterized by the dysregulation of the Syk/JAK pathway, the dosage form comprising micronized granules and extragranular components compressed into a tablet, and wherein:

• the micronized granules comprise:
• an active ingredient;
• one or more granulation binders;
• one or more fillers;
• one or more disintegrants;
• and one or more antioxidants;
• the extragranular components comprise one or more tableting fillers, one or more disintegrants, one or more lubricants, and optionally one or more surfactants;
• the active ingredient is a compound of Formula (I) or a pharmaceutically acceptable salt, enantiomer or prodrug thereof,
• wherein R1 is a 6-membered ring of Formula (II):
• wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or (C1 to C6) alkyl CN;
• and
• wherein R2 is a benzene ring of Formula (III):
• wherein R4 is a 6-membered ring of Formula (IV);
• wherein R5 is N or CH and R6 is a hydroxyl group, methanol group, or ethanol group, and wherein the formulation has a total API degradation impurity level not above about 0.6% of the total active ingredient amount after storage at 1 week at 40° C./75% RH in an open container.

A method of stabilizing a pharmaceutical formulation, the formulation being useful for treating one or more diseases characterized by the dysregulation of the Syk/JAK pathway, comprising:

• (a) mixing intragranular ingredients comprising an active ingredient;
• one or more fillers;
• one or more disintegrants;
• and one or more antioxidants;
• (b) granulating the mixed intragranular ingredients while adding a solution of 10% w/w of one or more granulation binders in 99% v/v isopropyl alcohol until granules are formed;
• (c) drying and milling the granules to make micronized granules:
• wherein the active ingredient comprises a compound of Formula (I) or a pharmaceutically acceptable salt, enantiomer or prodrug thereof:
• wherein R1 is a 6-membered ring of Formula (II):
• wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or (C1 to C6) alkyl CN;
• and
• wherein R2 is a benzene ring of Formula (III):
• wherein R4 is a 6-membered ring of Formula (IV);
• wherein R5 is N or CH and R6 is a hydroxyl group, methyl group, or ethyl group, wherein the formulation has a total API degradation impurity level not above about 0.6% of the total active ingredient amount after storage at 1 week at 40° C./75% RH in an open container.

A method of preparing a compressed tablet pharmaceutical formulation, the formulation used for treating one or more diseases characterized by the dysregulation of the Syk/JAK pathway, comprising:

• (a) mixing intragranular ingredients comprising an active ingredient;
• one or more fillers;
• one or more disintegrants;
• and one or more antioxidants;
• (b) granulating the mixed intragranular ingredients while adding a solution of 10% w/w of one or more granulation binders in 99% y/v isopropyl alcohol until granules are formed;
• (c) drying and milling the granules to make micronized granules;
• (d) mixing the micronized granules with extragranular components, the extragranular components comprising one or more tablering fillers, one or more disintegrants, one or more lubricants, and optionally one or more surfactants;
• and
• compressing the micronized granules with extragranular components into a tablet. wherein the active ingredient comprises a compound of Formula (1) or a pharmaceutically acceptable salt, enantiomer or prodrug thereof:
• wherein R1 is a 6-membered ring of Formula (II):
• wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or (C1 to C6) alkyl CN;
• and
• wherein R2 is a benzene ring of Formula (III):
• wherein R4 is a 6-membered ring of Formula (IV):
• wherein R5 is N or CH and R6 is a hydroxyl group, methyl group, or ethyl group, and wherein the formulation has a total API degradation impurity level not above about 0.6% of the total active ingredient amount after storage at 1 week at 40° C./75% RH in an open container.

A method of treating one or more diseases characterized by the dysregulation of the Syk/JAK pathway in a subject, comprising administering to the subject a therapeutically effective amount of an active ingredient in one or more dosage forms, wherein the dosage forms comprise micronized granules and extragranular components compressed into a tablet, and wherein:

• the micronized granules comprise:
• an active ingredient;
• one or more granulation binders;
• one or more fillers;
• one or more disintegrants;
• and one or more antioxidants;
• the extragranular components comprise one or more tableting fillers, one or more disintegrants, one or more lubricants, and optionally one or more surfactants;
• and
• the active ingredient is a compound of Formula (1) or a pharmaceutically acceptable salt, enantiomer or prodrug thereof,
• wherein R1 is a 6-membered ring of Formula (II):
• wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or (C1 to C6) alkyl CN;
• and
• wherein R2 is a benzene ring of Formula (III);
• wherein R4 is a 6-membered ring of Formula (IV):
• wherein R5 is N or CH and R6 is a hydroxyl group, methyl group, or ethyl group, and wherein the formulation has a total API degradation impurity level not above about 0.6% of the total active ingredient amount after storage at 1 week at 40° C./75% RH in an open container.

A method of manufacturing a pharmaceutical formulation, the formulation useful for treating one or more diseases characterized by the dysregulation of the Syk/JAK pathway, comprising:

• (a) mixing intragranular ingredients comprising an active ingredient;
• one or more fillers;
• one or more disintegrants;
• and one or more antioxidants;
• (b) granulating the mixed intragranular ingredients while adding a solution of 10% w/w of one or more granulation binders in 99% v/v isopropyl alcohol until granules are formed;
• (c) drying and milling the granules to make micronized granules;
• wherein the active ingredient comprises a compound of Formula (I) or a pharmaceutically acceptable salt, enantiomer or prodrug thereof:
• wherein R1 is a 6-membered ring of Formula (II):
• wherein R3 is H, OH, C(O)OH, C1 to C6 alkyl or (C1 to C6) alkyl CN;
• and
• wherein R2 is a benzene ring of Formula (III):
• wherein R4 is a 6-membered ring of Formula (IV):
• wherein R5 is N or CH and R6 is a hydroxyl group, methyl group, or ethyl group, wherein the formulation has a total API degradation impurity level not above about 0.6% of the total active ingredient amount after storage at 1 week at 40° C./75% RH in an open container.

A compressed tablet comprising micronized granules and extragranular components, wherein:

• the tablet has a total weight of about 150 mg;
• the micronized granules comprise about 5 to 50 mg of an active ingredient, about 118.6 to 736 mg of lactose monohydrate, about 4.5 mg croscarmellose sodium, about 0.15 mg vitamin E and about 4.5 mg granulation binder;
• and the extragranular components comprise about 11.25 mg microcrystalline cellulose, about 4.5 mg croscarmellose sodium and about 1.5 mg magnesium stearate, and about 6 mg of an enteric coating;
• and the active ingredient is 2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile.