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 composition formulated to prevent or reduce the photodegradation of an active ingredient [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, the composition comprising the active ingredient [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, and an effective amount of a photostabilizing agent, which photostabilizing agent:
 i) prevents the transmission of light at a wavelength range of between about 200 nm and 550 nm; and   ii) is admixed with the active ingredient, or provided in an outer coating or shell surrounding the active ingredient, such that the composition upon exposure to light contains less than about 0.2% w/w photodegradation product of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid relative to the amount of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the photostabilizing agent comprises titanium dioxide and at least one additional dye selected from the group consisting of a red dye, a yellow dye, and a combination of a red dye and a yellow dye. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the photostabilizing agent comprises titanium dioxide and at least one additional dye selected from the group consisting of iron oxide red, Allura Red AC, Allura Red AC Aluminum Lake, iron oxide yellow, Sunset Yellow FCF, and Sunset Yellow FCF Aluminum Lake, or a combination thereof. 
     
     
         4 . The pharmaceutical composition of  claim 1 , comprising from about 20 mg to about 200 mg of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. 
     
     
         5 . The pharmaceutical composition of  claim 1 , comprising about 20 mg, about 50 mg, or about 100 mg of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. 
     
     
         6 . A solid dosage form comprising the pharmaceutical composition of  claim 1 , wherein the solid dosage form is selected from capsule, tablet, bead, granule, pellet, lozenge, pill, or gum. 
     
     
         7 . The solid dosage form of  claim 6 , wherein the solid dosage form is tablet or capsule. 
     
     
         8 . A tablet comprising the pharmaceutical composition of  claim 1 , wherein
 (i) the photostabilizing agent is admixed with the active ingredient; or   (ii) the tablet comprises a tablet core and a coating and the photostabilizing agent is admixed with the active ingredient in the tablet core; or   (iii) the tablet comprises a tablet core and a coating and the tablet core comprises the active ingredient, and the coating comprises the photostabilizing agent.   
     
     
         9 . The tablet of  claim 8 , wherein the tablet comprises a tablet core and a coating and the tablet core comprises the active ingredient, and the coating comprises the photostabilizing agent, and further 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.   
     
     
         10 . The tablet of  claim 8 , wherein the tablet comprises a tablet core and a coating and the tablet core comprises the active ingredient, and the coating comprises the photostabilizing agent, and further 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 mg/cm 2  Sunset Yellow FCF in aluminum lake;   wherein the amount of photostabilizing agent is based on surface area of the tablet core.   
     
     
         11 . The tablet of  claim 8 , wherein the tablet comprises a tablet core and a coating and the tablet core comprises [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, and the coating comprises the photostabilizing agent, and the coating is present in an amount from about 3% to about 8% w/w (based on the weight of the tablet core). 
     
     
         12 . The tablet of  claim 11 , wherein the photostabilizing agent comprises titanium dioxide and Allura Red AC aluminum lake. 
     
     
         13 . The tablet of  claim 12 , 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, and wherein the amount of titanium dioxide and Allura Red AC in aluminum lake is based on surface area of the tablet core. 
     
     
         14 . The tablet of  claim 13 , 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 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. 
     
     
         15 . A capsule comprising the pharmaceutical composition of  claim 1 , wherein the capsule comprises a capsule fill and a capsule shell, and further wherein the capsule fill comprises an active ingredient [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]acetic acid, and a pharmaceutically acceptable excipient, and the capsule shell comprises an effective amount of a photostabilizing agent. 
     
     
         16 . The capsule of  claim 15 , wherein the capsule shell comprises from about 1.8% to about 6%, or from about 2% to about 3.5%, w/w photostabilizing agent (based on the weight of the capsule shell). 
     
     
         17 . The capsule of  claim 15 , wherein the photostabilizing agent comprises titanium dioxide and at least one additional dye selected from the group consisting of iron oxide red, Allura Red AC, and iron oxide yellow, or a combination thereof. 
     
     
         18 . A method of inhibiting the photodegradation of [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3carbonyl)-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. 
     
     
         19 . The method of  claim 18 , wherein the photostabilizing agent comprises titanium dioxide and at least one additional dye selected from the group consisting of a red dye, a yellow dye, and a combination of a red dye and a yellow dye. 
     
     
         20 . The method of  claim 18 , wherein the photostabilizing agent comprises titanium dioxide and at least one additional dye selected from the group consisting of iron oxide red, Allura Red AC, Allura Red AC Aluminum Lake, iron oxide yellow, Sunset Yellow FCF, and Sunset Yellow FCF Aluminum Lake, or a combination thereof.