Topical ocular delivery of cromakalim
An aqueous clear topical ocular solution of levcromakalim, or a pharmaceutically acceptable salt thereof, is provided in an effective therapeutic amount to treat the anterior portion of the human eye without the use of a covalent prodrug approach, a polymeric delivery system or a high level of toxic components, and with at least 4 months of shelf life stability, through the use of specifically discovered combinations of excipient components.
1 . An aqueous clear ocular topical pharmaceutically acceptable solution comprising:
(a) levcromakalim at a concentration between about 0.05 mM to about 5 mM;
(b) an ethoxylated glycerol ester;
(c) a polyethoxylated furanose fatty acid ester;
(d) a polymeric lactam;
(e) a nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene;
(f) a polyol; and
(g) water and phosphate buffer as aqueous components;
wherein the pH of the pharmaceutical composition is between 6 to 8.
2 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the concentration of levcromakalim is about 0.075% w/v (about 2.6 mM).
3 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the concentration of levcromakalim is about 0.03% w/v (about 1 mM).
4 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the concentration of levcromakalim is about 0.015% w/v (about 0.5 mM).
5 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the ethoxylated glycerol ester is polyoxyl-ethylated castor oil.
6 . The aqueous clear ocular topical pharmaceutical solution of claim 5 , wherein the concentration of polyoxyl-ethylated castor oil is about 4% w/v.
7 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the polyethoxylated furanose fatty acid ester is polysorbate 80.
8 . The aqueous clear ocular topical pharmaceutical solution of claim 7 , wherein the concentration of polysorbate 80 is about 1% w/v.
9 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the nonionic tri-block copolymer of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene is poloxamer 407.
10 . The aqueous clear ocular topical pharmaceutical solution of claim 9 wherein the concentration of poloxamer 407 is about 0.1% w/v.
11 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the polyol is mannitol.
12 . The aqueous clear ocular topical pharmaceutical solution of claim 11 , wherein the concentration of mannitol is about 3.3% w/v.
13 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the polymeric lactam is polyvinylpyrrolidone (PVP).
14 . The aqueous clear ocular topical pharmaceutical solution of claim 13 , wherein the polyvinylpyrrolidone (PVP) is povidone K-30.
15 . The aqueous clear ocular topical pharmaceutical solution of claim 14 , wherein the concentration of povidone K-30 is about 2% w/v.
16 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the phosphate buffer is a sodium phosphate monobasic buffer, sodium phosphate dibasic buffer, or a mixture thereof.
17 . The aqueous clear ocular topical pharmaceutical solution of claim 16 , wherein the concentration of sodium phosphate monobasic buffer is about 0.09% w/v.
18 . The aqueous clear ocular topical pharmaceutical solution of claim 16 , wherein the concentration of sodium phosphate dibasic buffer is about 0.09% w/v.
19 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the composition further comprises a pH adjusting agent.
20 . The aqueous clear ocular topical pharmaceutical solution of claim 19 , wherein the pH adjusting agent is hydrochloric acid.
21 . The aqueous clear ocular topical pharmaceutical solution of claim 1 , wherein the pH of the composition is about 6.5.
22 . An aqueous clear ocular topical pharmaceutical solution comprising:
(a) levcromakalim at a concentration of about 0.015% w/v;
(b) polyoxyl-ethylated castor oil at a concentration of about 4% w/v;
(c) polysorbate 80 at a concentration of about 1% w/v;
(d) polyvinylpyrrolidone (PVP) at a concentration of about 2% w/v;
(e) poloxamer 407 at a concentration of about 0.1% w/v;
(f) mannitol at a concentration of about 3.3% w/v; and
further comprising water and phosphate buffer as aqueous components;
wherein the pharmaceutical composition has a pH of about 6.5.
23 . An aqueous clear ocular topical pharmaceutical solution comprising:
(a) levcromakalim at a concentration of about 0.030% w/v;
(b) polyoxyl-ethylated castor oil at a concentration of about 4% w/v;
(c) polysorbate 80 at a concentration of about 1% w/v;
(d) polyvinylpyrrolidone (PVP) at a concentration of about 2% w/v;
(e) poloxamer 407 at a concentration of about 0.1% w/v;
(f) mannitol at a concentration of about 3.3% w/v; and
further comprising water and phosphate buffer as aqueous components;
wherein the pharmaceutical composition has a pH of about 6.5.
24 . An aqueous clear ocular topical pharmaceutical solution comprising:
(a) levcromakalim at a concentration of about 0.075% w/v;
(b) polyoxyl-ethylated castor oil at a concentration of about 4% w/v;
(c) polysorbate 80 at a concentration of about 1% w/v;
(d) polyvinylpyrrolidone (PVP) at a concentration of about 2% w/v;
(e) poloxamer 407 at a concentration of about 0.1% w/v;
(f) mannitol at a concentration of about 3.3% w/v; and
further comprising water and phosphate buffer as aqueous components;
wherein the pharmaceutical composition has a pH of about 6.5.