PHARMACEUTICAL COMPOSITIONS COMPRISING DGLA AND USE OF SAME
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.