Pharmaceutical compositions comprising dgla and use of same

Abstract

The present disclosure provides orally deliverable pharmaceutical compositions comprising DGLA and to methods of using same to treat a variety of conditions and disorders.

1 .- 27 . (canceled) 
     
     
         28 . A pharmaceutical composition comprising at least about 80% dihomo gamma linolenic acid (DGLA), by weight of total fatty acids. 
     
     
         29 . The pharmaceutical composition of  claim 28  further comprising eicosatetraenoic acid. 
     
     
         30 . The pharmaceutical composition of  claim 28  further comprising oleic acid. 
     
     
         31 . The pharmaceutical composition of  claim 28 , wherein up to about 1 g of the composition is encapsulated in a capsule shell. 
     
     
         32 . The pharmaceutical composition of  claim 29 , wherein up to about 1 g of the composition is encapsulated in a capsule shell. 
     
     
         33 . The pharmaceutical composition of  claim 30 , wherein up to about 1 g of the composition is encapsulated in a capsule shell. 
     
     
         34 . The pharmaceutical composition of  claim 28 , comprising up to about 1 g of dihomo gamma linolenic acid and wherein the composition comprises not more than 5%, by weight of total fatty acids, of any individual fatty acid other than dihomo gamma linolenic acid. 
     
     
         35 . The pharmaceutical composition of  claim 28 , wherein upon oral administration of a single dose of said composition comprising about 100 mg to about 8000 mg of DGLA to a fasted subject the subject exhibits one or more of the following outcomes:
 (a) a free DGLA Cmax of about 700 ng/ml to about 3200 ng/ml;   (b) a free DGLA AUC0-24 of about 2500 ng·h/ml to about 10000 ng·h/ml;   (c) a free DGLA AUC0-24/dose of about 2 to about 6 h/kL;   (d) a free DGLA tmax (h) of about 3 to about 8 hours;   (e) a total DGLA Cmax of about 7000 ng/ml to about 32000 ng/ml;   (f) a total DGLA AUC0-24 of about 25,000 ng·h/ml to about 225,000 ng·h/ml;   (g) a total DGLA AUC0-24/dose 70 to about 225 h/kL;   (h) a total DGLA tmax (h) of about 3 to about 20 hours;   (i) a total DGLA Cmax/dose of about 2 (1/kL) to about 25 (1/kl), about 4 (1/kl) to about 20 (1/kl) or about 5 (1/kl) to about 17 (1/kl);   (j) a free DGLA Cmax/dose of about 0.3 (1/kL) to about 2.5 (1/kL)   (k) a ratio of total DGLA Cmax to free DGLA Cmax of about 7:1 to about 9:1; and/or   (l) a ratio of free DGLA plasma to DGLA skin as measured in skin blister fluid from about 0.6:1 to about 1.5:1.   
     
     
         36 . The pharmaceutical composition of  claim 28 , wherein upon oral administration of multiple daily doses of said composition to a fasted subject for a period of about 2 to about 30 days, each daily dose comprising about 100 mg to about 8000 mg of DGLA, the subject exhibits one or more of the following outcomes:
 (a) a steady state free DGLA plasma level (Cavg) of up to about 2000 ng/ml, up to about 750 ng/ml, or up to about 350 ng/ml;   (b) a steady state total DGLA plasma level (Cavg) of up to 250,000 ng/ml, up to 180,000 ng/ml, up to 150,000 ng/ml, up to 125,000 ng/ml or up to 100,000 ng/ml; and/or   (c) a ratio of free DGLA plasma to DGLA as measured in skin blister fluid from about 0.2:1 to about 5:1, about 0.5:1 to about 2.5:1 or about 0.6:1 to about 1.5:1.   
     
     
         37 . The pharmaceutical composition of  claim 28 , wherein upon oral administration of multiple daily doses of said composition to a fasted subject and to a fed subject for a period of about 2 to about 30 days, each daily dose comprising about 100 mg to about 8000 mg of DGLA, the subjects exhibit:
 (a) a ratio of free DGLA Cmax fasted:fed of between 1:1 to 5:1; of about 2.5:1, of about 3:1 or of about 3.5:1;   (b) a ratio of free DGLA AUC0-24 fasted:fed of between 1:1 to 5:1; of about 1.5:1, of about 2:1 or of about 2.5:1;   (c) a ratio of total DGLA Cmax fasted:fed of between 1:1 to 5:1; of about 1:1, of about 1.5:1 or of about 2:1; and/or   (d) a ratio of total DGLA AUC0-24 fasted:fed of between 1:1 to 5:1; of about 1.5:1, of about 2:1 or of about 2.5:1.   
     
     
         38 . A pharmaceutical composition comprising at least about 90% dihomo gamma linolenic acid, by weight of total fatty acids. 
     
     
         39 . The pharmaceutical composition of  claim 38  further comprising eicosatetraenoic acid. 
     
     
         40 . The pharmaceutical composition of  claim 38  further comprising oleic acid. 
     
     
         41 . The pharmaceutical composition of  claim 38 , wherein up to about 1 g of the composition is encapsulated in the capsule shell. 
     
     
         42 . The pharmaceutical composition of  claim 39 , wherein up to about 1 g of the composition is encapsulated in the capsule shell. 
     
     
         43 . The pharmaceutical composition of  claim 40 , wherein up to about 1 g of the composition is encapsulated in the capsule shell. 
     
     
         44 . The pharmaceutical composition of  claim 38 , comprising up to about 1 g of dihomo gamma linolenic acid and wherein the composition comprises not more than 5%, by weight of total fatty acids, of any individual fatty acid other than dihomo gamma linolenic acid. 
     
     
         45 . The pharmaceutical composition of  claim 38 , wherein upon oral administration of a single dose of said composition comprising about 100 mg to about 8000 mg of DGLA to a fasted subject the subject exhibits one or more of the following outcomes:
 (a) a free DGLA Cmax of about 700 ng/ml to about 3200 ng/ml;   (b) a free DGLA AUC0-24 of about 2500 ng·h/ml to about 10000 ng·h/ml;   (c) a free DGLA AUC0-24/dose of about 2 to about 6 h/kL;   (d) a free DGLA tmax (h) of about 3 to about 8 hours;   (e) a total DGLA Cmax of about 7000 ng/ml to about 32000 ng/ml;   (f) a total DGLA AUC0-24 of about 25,000 ng·h/ml to about 225,000 ng·h/ml;   (g) a total DGLA AUC0-24/dose 70 to about 225 h/kL;   (h) a total DGLA tmax (h) of about 3 to about 20 hours;   (i) a total DGLA Cmax/dose of about 2 (1/kL) to about 25 (1/kl), about 4 (1/kl) to about 20 (1/kl) or about 5 (1/kl) to about 17 (1/kl);   (j) a free DGLA Cmax/dose of about 0.3 (1/kL) to about 2.5 (1/kL)   (k) a ratio of total DGLA Cmax to free DGLA Cmax of about 7:1 to about 9:1; and/or   (l) a ratio of free DGLA plasma to DGLA skin as measured in skin blister fluid from about 0.6:1 to about 1.5:1.   
     
     
         46 . The pharmaceutical composition of  claim 38 , wherein upon oral administration of multiple daily doses of said composition to a fasted subject over a period of about 2 to about 30 days, each daily dose comprising about 100 mg to about 8000 mg of DGLA, the subject exhibits one or more of the following outcomes:
 (a) a steady state free DGLA plasma level (Cavg) of up to about 2000 ng/ml, up to about 750 ng/ml, or up to about 350 ng/ml;   (b) a steady state total DGLA plasma level (Cavg) of up to 250,000 ng/ml, up to 180,000 ng/ml, up to 150,000 ng/ml, up to 125,000 ng/ml or up to 100,000 ng/ml; and/or   (c) a ratio of free DGLA plasma to DGLA as measured in skin blister fluid from about 0.2:1 to about 5:1, about 0.5:1 to about 2.5:1 or about 0.6:1 to about 1.5:1.   
     
     
         47 . The pharmaceutical composition of  claim 38 , wherein upon oral administration of multiple daily doses of said composition to a fasted subject and to a fed subject over a period of about 2 to about 30 days, each daily dose comprising about 100 mg to about 8000 mg of DGLA, the subjects exhibit:
 (a) a ratio of free DGLA Cmax fasted:fed of between 1:1 to 5:1; of about 2.5:1, of about 3:1 or of about 3.5:1;   (b) a ratio of free DGLA AUC0-24 fasted:fed of between 1:1 to 5:1; of about 1.5:1, of about 2:1 or of about 2.5:1;   (c) a ratio of total DGLA Cmax fasted:fed of between 1:1 to 5:1; of about 1:1, of about 1.5:1 or of about 2:1; and/or   (d) a ratio of total DGLA AUC0-24 fasted:fed of between 1:1 to 5:1; of about 1.5:1, of about 2:1 or of about 2.5:1.   
     
     
         48 . A pharmaceutical composition comprising at least about 95% dihomo gamma linolenic acid, by weight of total fatty acids. 
     
     
         49 . The pharmaceutical composition of  claim 48  further comprising eicosatetraenoic acid. 
     
     
         50 . The pharmaceutical composition of  claim 48  further comprising oleic acid. 
     
     
         51 . The pharmaceutical composition of  claim 48 , wherein up to about 1 g of the composition is encapsulated in the capsule shell. 
     
     
         52 . The pharmaceutical composition of  claim 49 , wherein up to about 1 g of the composition is encapsulated in the capsule shell. 
     
     
         53 . The pharmaceutical composition of  claim 50 , wherein up to about 1 g of the composition is encapsulated in the capsule shell. 
     
     
         54 . The pharmaceutical composition of  claim 48 , comprising up to about 1 g of dihomo gamma linolenic acid and wherein the composition comprises not more than 5%, by weight of total fatty acids, of any individual fatty acid other than dihomo gamma linolenic acid. 
     
     
         55 . The pharmaceutical composition of  claim 48 , wherein upon oral administration of a single dose of said composition comprising about 100 mg to about 8000 mg of DGLA to a fasted subject the subject exhibits one or more of the following outcomes:
 (a) a free DGLA Cmax of about 700 ng/ml to about 3200 ng/ml;   (b) a free DGLA AUC0-24 of about 2500 ng·h/ml to about 10000 ng·h/ml;   (c) a free DGLA AUC0-24/dose of about 2 to about 6 h/kL;   (d) a free DGLA tmax (h) of about 3 to about 8 hours;   (e) a total DGLA Cmax of about 7000 ng/ml to about 32000 ng/ml;   (f) a total DGLA AUC0-24 of about 25,000 ng·h/ml to about 225,000 ng·h/ml;   (g) a total DGLA AUC0-24/dose 70 to about 225 h/kL;   (h) a total DGLA tmax (h) of about 3 to about 20 hours;   (i) a total DGLA Cmax/dose of about 2 (1/kL) to about 25 (1/kl), about 4 (1/kl) to about 20 (1/kl) or about 5 (1/kl) to about 17 (1/kl);   (j) a free DGLA Cmax/dose of about 0.3 (1/kL) to about 2.5 (1/kL)   (k) a ratio of total DGLA Cmax to free DGLA Cmax of about 7:1 to about 9:1; and/or   (l) a ratio of free DGLA plasma to DGLA skin as measured in skin blister fluid from about 0.6:1 to about 1.5:1.   
     
     
         56 . The pharmaceutical composition of  claim 48 , wherein upon oral administration of multiple daily doses of said composition to a fasted subject over a period of about 2 to about 30 days, each daily dose comprising about 100 mg to about 8000 mg of DGLA, the subject exhibits one or more of the following outcomes:
 (a) a steady state free DGLA plasma level (Cavg) of up to about 2000 ng/ml, up to about 750 ng/ml, or up to about 350 ng/ml;   (b) a steady state total DGLA plasma level (Cavg) of up to 250,000 ng/ml, up to 180,000 ng/ml, up to 150,000 ng/ml, up to 125,000 ng/ml or up to 100,000 ng/ml; and/or   (c) a ratio of free DGLA plasma to DGLA as measured in skin blister fluid from about 0.2:1 to about 5:1, about 0.5:1 to about 2.5:1 or about 0.6:1 to about 1.5:1.   
     
     
         57 . The pharmaceutical composition of  claim 48 , wherein upon oral administration of multiple daily doses of said composition to a fasted subject and to a fed subject for a period of about 2 to about 30 days, each daily dose comprising about 100 mg to about 8000 mg of DGLA, the subjects exhibit:
 (a) a ratio of free DGLA Cmax fasted:fed of between 1:1 to 5:1; of about 2.5:1, of about 3:1 or of about 3.5:1;   (b) a ratio of free DGLA AUC0-24 fasted:fed of between 1:1 to 5:1; of about 1.5:1, of about 2:1 or of about 2.5:1;   (c) a ratio of total DGLA Cmax fasted:fed of between 1:1 to 5:1; of about 1:1, of about 1.5:1 or of about 2:1; and/or   (d) a ratio of total DGLA AUC0-24 fasted:fed of between 1:1 to 5:1; of about 1.5:1, of about 2:1 or of about 2.5:1.