Pharmaceutical formulations of a hif hydroxylase inhibitor

Abstract

The present disclosure relates to pharmaceutical formulations of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid and methods of use thereof.

What is claimed is: 
     
         1 . A pharmaceutical formulation comprising [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, a pharmaceutically acceptable excipient, and an effective amount of a photostabilizing agent, wherein the pharmaceutical formulation comprises less than about 0.2% w/w (based on the amount of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid) photodegradation product of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. 
     
     
         2 . A pharmaceutical formulation comprising [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, a pharmaceutically acceptable excipient, and an effective amount of a photostabilizing agent, wherein the photostabilizing agent comprises titanium dioxide and at least one additional dye. 
     
     
         3 . The pharmaceutical formulation of  claim 1  or  2 , wherein the photostabilizing agent blocks light at a wavelength range of between about 200 and about 550 nm. 
     
     
         4 . The pharmaceutical formulation of  claim 2 , wherein the dye is selected from the group consisting of a black dye, a blue dye, a green dye, a red dye, an orange dye, a yellow dye, and combinations thereof. 
     
     
         5 . The pharmaceutical formulation of  claim 4 , wherein the dye is selected from the group consisting of a red dye, an orange dye, a yellow dye, and combinations thereof. 
     
     
         6 . The pharmaceutical formulation of  claim 4 , wherein the dye is selected from the group consisting of Allura Red AC, Allura Red AC aluminum lake, iron oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset Yellow FCF aluminum lake, Indigotine, Indigotine aluminum lake, and combinations thereof. 
     
     
         7 . The pharmaceutical formulation of any one of  claims 1 - 6 , comprising from about 20 mg to about 200 mg of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. 
     
     
         8 . The pharmaceutical formulation of  claim 7 , comprising about 20 mg, about 50 mg, or about 100 mg of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. 
     
     
         9 . The pharmaceutical formulation of  claim 7 , comprising about 20 mg or about 50 mg of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. 
     
     
         10 . The pharmaceutical formulation of any one of  claims 1 - 9 , wherein the photostabilizing agent comprises titanium dioxide and Allura Red AC aluminum lake. 
     
     
         11 . The pharmaceutical formulation of any one of  claims 1 - 9 , wherein the photostabilizing agent comprises iron oxide red and titanium dioxide. 
     
     
         12 . The pharmaceutical formulation of any one of  claims 1 - 9 , wherein the photostabilizing agent comprises Allura Red AC, iron oxide yellow, and titanium dioxide. 
     
     
         13 . The pharmaceutical formulation of any one of  claims 1 - 9 , wherein the photostabilizing agent comprises iron oxide red, Allura Red AC, iron oxide yellow, and titanium dioxide. 
     
     
         14 . The pharmaceutical formulation of any one of  claims 1 - 9 , wherein the photostabilizing agent comprises iron oxide red, iron oxide yellow, and titanium dioxide. 
     
     
         15 . The pharmaceutical formulation of any one of  claims 1 - 9 , wherein the photostabilizing agent comprises iron oxide yellow and titanium dioxide. 
     
     
         16 . A solid dosage form comprising the pharmaceutical formulation of any one of  claims 1 - 9 , wherein the solid dosage form is selected from capsule, tablet, bead, granule, pellet, lozenge, pill, or gum. 
     
     
         17 . The solid dosage form of  claim 16 , wherein the solid dosage form is tablet. 
     
     
         18 . The solid dosage form of  claim 16 , wherein the solid dosage form is capsule. 
     
     
         19 . A tablet comprising [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, a pharmaceutically acceptable excipient, and an effective amount of a photostabilizing agent. 
     
     
         20 . The tablet of  claim 19 , comprising a tablet core and a coating. 
     
     
         21 . The tablet of  claim 19  or  20 , wherein the photostabilizing agent is blended into the tablet or the tablet core. 
     
     
         22 . The tablet of  claim 20 , wherein the tablet core comprises [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid and the pharmaceutically acceptable excipient, and the coating comprises the photostabilizing agent. 
     
     
         23 . The tablet of  claim 21  or  22 , wherein the photostabilizing agent comprises titanium dioxide and at least one additional dye selected from the group consisting of Allura Red AC, Allura Red AC aluminum lake, iron oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset Yellow FCF aluminum lake, Indigotine, Indigotine aluminum lake, and combinations thereof. 
     
     
         24 . The tablet of  claim 23 , wherein the photostabilizing agent comprises titanium dioxide and Allura Red AC aluminum lake. 
     
     
         25 . The tablet of  claim 22 , wherein the photostabilizing agent comprises at least about 0.1 mg/cm 2  titanium dioxide and at least one additional dye selected from the group consisting of:
 at least about 0.1 mg/cm 2  Allura Red AC;   at least about 0.1 mg/cm 2  Allura Red AC in aluminum lake;   at least about 0.004 mg/cm 2  iron oxide red;   at least about 0.009 mg/cm 2  iron oxide yellow;   at least about 0.01 mg/cm 2  Sunset Yellow FCF; and   at least about 0.01 mg/cm 2  Sunset Yellow FCF in aluminum lake;   wherein the amount of photostabilizing agent is based on surface area of the tablet core.   
     
     
         26 . The tablet of  claim 22 , wherein the photostabilizing agent comprises, from about 0.1 to about 2 mg/cm 2  titanium dioxide and at least one additional dye selected from the group consisting of:
 from about 0.1 to about 0.4 mg/cm 2  Allura Red AC;   from about 0.1 to about 0.4 mg/cm 2  Allura Red AC in aluminum lake;   from about 0.004 to about 0.4 mg/cm 2  iron oxide red;   from about 0.009 to about 0.2 mg/cm 2  iron oxide yellow;   from about 0.01 to 0.03 mg/cm 2  Sunset Yellow FCF; and   from about 0.01 to 0.03 ma/cm 2  Sunset Yellow FCF in aluminum lake;   wherein the amount of photostabilizing agent is based on surface area of the tablet core.   
     
     
         27 . A tablet comprising a tablet core and a coating, wherein the tablet core comprises [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid and a pharmaceutically acceptable excipient, and the coating comprises an effective amount of a photostabilizing agent, wherein the coating is present in an amount from about 3% to about 8% w/w (based on the weight of the tablet core). 
     
     
         28 . The tablet of  claim 27 , wherein the tablet core comprises from about 22% to about 28% w/w [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (based on the weight of the tablet core) and a pharmaceutically acceptable excipient. 
     
     
         29 . The tablet of  claim 28 , wherein the pharmaceutically acceptable excipient comprises lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate. 
     
     
         30 . The tablet of  claim 28  or  29 , wherein the tablet core comprises from about 20 mg to about 200 mg [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. 
     
     
         31 . The tablet of  claim 30 , wherein the tablet core comprises about 20 mg, about 50 mg or about 100 mg [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. 
     
     
         32 . The tablet of  claim 27 , wherein the photostabilizing agent comprises titanium dioxide and at least one additional dye selected from the group consisting of Allura Red AC, Allura Red AC aluminum lake, iron oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset Yellow FCF aluminum lake, Indigotine, Indigotine aluminum lake, and combinations thereof. 
     
     
         33 . The tablet of  claim 32 , wherein the photostabilizing agent comprises titanium dioxide and Allura Red AC aluminum lake. 
     
     
         34 . The tablet of  claim 33 , wherein the coating comprises from about 0.1 to about 0.4 mg/cm 2  titanium dioxide and from about 0.1 to about 0.4 mg/cm 2  Allura Red AC in aluminum lake wherein the amount of titanium dioxide and Allura Red AC in aluminum lake is based on surface area of the tablet core. 
     
     
         35 . The tablet of  claim 27 , wherein the tablet core comprises about 20 mg, about 50 mg or about 100 mg of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and wherein the photostabilizing agent comprises 0.1 to about 0.4 mg/cm 2  titanium dioxide and from about 0.1 to about 0.4 ing/cm 2  Allura Red AC in aluminum lake wherein the amount of titanium dioxide and Miura Red AC in aluminum lake is based on surface area of the tablet core. 
     
     
         36 . A capsule comprising [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, a pharmaceutically acceptable excipient and an effective amount of a photostabilizing agent. 
     
     
         37 . The capsule of  claim 36 , comprising a capsule fill and a capsule shell, wherein the capsule fill comprises [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid and the pharmaceutically acceptable excipient, and the capsule shell comprises the photostabilizing agent. 
     
     
         38 . The capsule of  claim 37 , wherein the photostabilizing agent comprises titanium dioxide and at least one additional dye selected from the group consisting of Allura Red AC, iron oxide red, iron oxide yellow, and combinations thereof. 
     
     
         39 . The capsule of  claim 38 , wherein the photostabilizing agent comprises iron oxide red and titanium dioxide. 
     
     
         40 . The capsule of  claim 38 , wherein the photostabilizing agent comprises Allura Red AC, iron oxide yellow, and titanium dioxide. 
     
     
         41 . The capsule of  claim 38 , wherein the photostabilizing agent comprises iron oxide red, Allura Red AC, iron oxide yellow, and titanium dioxide. 
     
     
         42 . The capsule of  claim 38 , wherein the photostabilizing agent comprises iron oxide red, iron oxide yellow, and titanium dioxide. 
     
     
         43 . The capsule of  claim 38 , wherein the photostabilizing agent comprises iron oxide yellow and titanium dioxide. 
     
     
         44 . The capsule of  claim 37 , wherein the capsule shell comprises from about 1.8% to about 6% w/w photostabilizing agent (based on the weight of the capsule shell). 
     
     
         45 . The capsule of  claim 37 , wherein the capsule shell comprises from about 2% to about 3.5% w/w photostabilizing agent (based on the weight of the capsule shell). 
     
     
         46 . The capsule of  claim 37 , wherein the capsule shell is a gelatin shell. 
     
     
         47 . A capsule comprising a capsule fill and a capsule shell, wherein the capsule fill comprises from about 12% to about 15% w/w [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (based on the weight of the capsule fill) and a pharmaceutically acceptable excipient, and wherein the capsule shell comprises an effective amount of a photostabilizing agent. 
     
     
         48 . The capsule of  claim 47 , wherein the pharmaceutically acceptable excipient comprises lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate. 
     
     
         49 . The capsule of  claim 47  or  48 , wherein the capsule fill comprises about 20 mg or about 50 mg [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. 
     
     
         50 . The capsule of  claim 47 , wherein the capsule shell comprises from about 2% w/w to about 3.5% w/w photostabilizing agent (based on the weight of the capsule shell). 
     
     
         51 . The capsule of  claim 47 , wherein the capsule fill comprises about 20 mg or about 50 mg [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and wherein the capsule shell is a gelatin shell comprising about 2% w/w iron oxide red and about 0.9% w/w titanium dioxide (based on the weight of the capsule shell). 
     
     
         52 . The capsule of  claim 47 , wherein the capsule fill comprises about 20 mg or about 50 mg [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and wherein the capsule shell is a gelatin shell comprising about 0.3% w/w Allura Red AC, about 1% w/w iron oxide yellow, and about 1% w/w titanium dioxide (based on the weight of the capsule shell). 
     
     
         53 . The capsule of  claim 47 , wherein the capsule fill comprises about 20 mg or about 50 mg [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and wherein the capsule shell is a gelatin shell comprising about 0.7% w/w iron oxide red, about 0.3% w/w Allura Red AC, about 1% w/w iron oxide yellow, and about 1% w/w titanium dioxide (based on the weight of the capsule shell). 
     
     
         54 . The capsule of  claim 47 , wherein the capsule fill comprises about 20 mg or about 50 mg [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and wherein the capsule shell is a gelatin shell comprising about 1% w/w iron oxide red, about 1% w/w iron oxide yellow, and about 1% w/w titanium dioxide (based on the weight of the capsule shell). 
     
     
         55 . The capsule of  claim 47 , wherein the capsule fill comprises about 20 mg or about 50 mg [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and wherein the capsule shell is a gelatin shell comprising about 1% w/w Allura Red AC, about 1% w/w iron oxide yellow, and about 1% w/w titanium dioxide (based on the weight of the capsule shell). 
     
     
         56 . The capsule of  claim 47 , wherein the capsule fill comprises about 20 mg or about 50 mg [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and wherein the capsule shell is a gelatin shell comprising about 2% w/w iron oxide red, and about 1% w/w titanium dioxide (based on the weight of the capsule shell). 
     
     
         57 . The capsule of  claim 47 , wherein the capsule fill comprises about 20 mg or about 50 mg [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and wherein the capsule shell is a gelatin shell comprising about 2% why iron oxide yellow, and about 1% w/w titanium dioxide (based on the weight of the capsule shell). 
     
     
         58 . A method of inhibiting the photodegradation of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, said method comprising formulating [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid with an effective amount of a photostabilizing agent. 
     
     
         59 . The method of  claim 58 , wherein the photostabilizing agent comprises titanium dioxide and at least one additional dye. 
     
     
         60 . A method for treating, preheating, or delaying onset or progression of a condition mediated at least in part by hypoxia inducible factor (HIF), comprising administering to a patient in need thereof, a pharmaceutical formulation of any one of  claims 1 - 15 , a tablet of any one of  claims 19 - 35 , or a capsule of any one of  claims 36 - 57 . 
     
     
         61 . A method for treating, pretreating, or delaying onset or progression of anemia, comprising administering to a patient in need thereof, a pharmaceutical formulation of any one of  claims 1 - 15 , a tablet of any one of  claims 19 - 35 , or a capsule of any one of  claims 36 - 57 .