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

Abstract

Embodiments of the disclosure relate generally to formulations, methods of treatment, kits, and dosage forms for treating inflammatory disorders, including atopic dermatitis, or cancer, the formulations comprising an active pharmaceutical ingredient. The formulation provided comprises granules, wherein the granules comprise: micronized active ingredient; one or more granulation binders; one or more fillers; one or more disintegrants; and one or more antioxidants. In one embodiment, the methods of treatment include orally administering the active ingredient to a subject suffering from atopic dermatitis, where the active ingredient is in an amount of about 20 mg to about 80 mg.

1 . A pharmaceutical formulation for treating one or more diseases characterized by the dysregulation of the Syk/JAK pathway, comprising granules, wherein the granules comprise: micronized active ingredient; one or more granulation binders; one or more fillers; one or more disintegrants; and one or more antioxidants, and 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 methyl group, or ethanol 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. 
       
     
     
         2 . The formulation of  claim 1 , wherein the one or more antioxidants comprise at least one of vitamin E or butylated hydroxytoluene. 
     
     
         3 . The formulation of  claim 2 , wherein the one or more antioxidants is vitamin E. 
     
     
         4 . The formulation of  claim 1 , wherein the micronized granules have a particle size of less than about 20 microns. 
     
     
         5 . The formulation of  claim 1 , wherein the one or more fillers comprise lactose monohydrate and the one or more distintegrants comprise crospovidone. 
     
     
         6 . The formulation of  claim 1 , wherein one or more granulation binders are selected from the group consisting of polyvinylpyrollidone and hydroxypropylcellulose. 
     
     
         7 . The formulation of  claim 6 , wherein the one or more granulation binders comprise polyvinylpyrollidone having a number average molecular weight of about 30,000. 
     
     
         8 . The formulation of  claim 6 , wherein the one or more granulation binders comprise hydroxypropylcellulose having a viscosity at 25° C. of 75-150 centipoise in a 5% w/w in aqueous solution. 
     
     
         9 . The formulation of  claim 1 , wherein the micronized granules have an isopropyl alcohol content of less than about 5000 ppm. 
     
     
         10 . The formulation of  claim 1 , wherein the granules are compressed into a tablet. 
     
     
         11 . The formulation of  claim 1 , further comprising one or more extragranular components. 
     
     
         12 . The formulation of  claim 11 , wherein the extragranular components comprise one or more tableting fillers, one or more disintegrants, one or more lubricants, and optionally one or more surfactants. 
     
     
         13 . The formulation of  claim 12 , wherein the one or more tableting fillers comprise microcrystalline cellulose, the one or more disintegrants comprise croscarmellose sodium, the one or more surfactants comprise sodium lauryl sulfate, and the one or more lubricants comprise magnesium stearate. 
     
     
         14 . The formulation of  claim 13 , wherein the micronized granules and extragranular components are compressed into a tablet. 
     
     
         15 . The formulation of  claim 14 , wherein the micronized granules have an isopropyl alcohol content of less than about 5000 ppm. 
     
     
         16 . The formulation of  claim 14 , wherein the amount of active ingredient per tablet is between about 5 to 50 mg. 
     
     
         17 . The formulation of  claim 14 , wherein the amount of active ingredient per tablet is between about 20 to 80 mg. 
     
     
         18 . The formulation of  claim 16 , wherein the amount of active ingredient per tablet is about 5 mg, about 20 mg, or about 50 mg. 
     
     
         19 . The formulation of  claim 17 , wherein the amount of active ingredient per tablet is about 20 mg, about 40 mg, or about 80 mg. 
     
     
         20 . The formulation of  claim 14 , wherein the tablet has a hardness of about 7 to 9 kP and a disintegration time of less than about 5 minutes in 0.1 N HCl, pH 6.8 and 50 mM phosphate buffer at 37° C. 
     
     
         21 . The formulation of  claim 14 , wherein the tablet comprises an aesthetic coating. 
     
     
         22 . The formulation of  claim 21 , wherein the coating is comprising of hydroxypropylcellulose, titanium dioxide, talc and polyethylene glycol. 
     
     
         23 . The formulation of  claim 14 , wherein 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. 
     
     
         24 . The formulation of  claim 14 , wherein the active ingredient is 2-(1-(4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile. 
     
     
         25 . The formulation of  claim 1 , wherein the disease comprises one or more cancers. 
     
     
         26 . The formulation of  claim 1 , wherein the disease comprises one or more inflammatory disorders. 
     
     
         27 . The formulation of  claim 26 , wherein the inflammatory disorders comprise atopic dermatitis. 
     
     
         28 . 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. 
         
       
     
     
         29 . The kit of  claim 27 , wherein the disease comprises one or more cancers. 
     
     
         30 . The kit of  claim 27 , wherein the disease comprises one or more inflammatory disorders. 
     
     
         31 . The kit of  claim 30 , wherein the inflammatory disorders comprise atopic dermatitis. 
     
     
         32 . The kit of  claim 31 , wherein the dosage form comprises the active ingredient in a dose of about 20 mg to about 80 mg. 
     
     
         33 . 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. 
         
       
     
     
         34 . The dosage form of  claim 31 , wherein the disease comprises or one or more cancers. 
     
     
         35 . The dosage form of  claim 31 , wherein the disease comprises one or more inflammatory disorders. 
     
     
         36 . The dosage form of  claim 35 , wherein the inflammatory disorders comprise atopic dermatitis. 
     
     
         37 . The dosage form of  claim 36 , wherein the active ingredient is in an amount of about 20 mg to about 80 mg. 
     
     
         38 . 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. 
       
     
     
         39 . The method of  claim 38 , wherein the disease comprises one or more cancers. 
     
     
         40 . The method of  claim 38 , wherein the disease comprises one or more inflammatory disorders. 
     
     
         41 . The method of  claim 40 , wherein the inflammatory disorders comprise atopic dermatitis. 
     
     
         42 . The method of  claim 41 , wherein the active ingredient is in an amount of about 20 mg to about 80 mg. 
     
     
         43 . 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% v/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 tableting 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 (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. 
         
       
     
     
         44 . The method of  claim 43 , wherein the disease comprises one or more cancers. 
     
     
         45 . The method of  claim 43 , wherein the disease comprises one or more inflammatory disorders. 
     
     
         46 . The method of  claim 45 , wherein the inflammatory disorders comprise atopic dermatitis. 
     
     
         47 . 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 (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. 
         
       
     
     
         48 . The method of  claim 47 , wherein the disease comprises one or more cancers. 
     
     
         49 . The method of  claim 47 , wherein the disease comprises one or more inflammatory disorders. 
     
     
         50 . The method of  claim 49 , wherein the inflammatory disorders comprise atopic dermatitis. 
     
     
         51 . The method of  claim 50  wherein the active ingredient is in an amount of about 20 mg to about 80 mg. 
     
     
         52 . 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. 
         
       
     
     
         53 . The method of  claim 52 , wherein the disease comprises one or more cancers. 
     
     
         54 . The method of  claim 52 , wherein the disease comprises one or more inflammatory disorders. 
     
     
         55 . The method of  claim 54 , wherein the inflammatory disorders comprise atopic dermatitis. 
     
     
         56 . 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.