Topical ocular delivery of cromakalim

Patent metadata

Field	Value
Publication number	US-12564572-B2
Application number	US-202418907296-A
Country	US
Kind code	B2
Filing date	Oct 4, 2024
Priority date	Nov 4, 2022
Publication date	Mar 3, 2026
Grant date	Mar 3, 2026

Abstract

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.

First claim

We claim:

1 . A method of treating an ocular disorder comprising administering an effective amount of an aqueous clear ocular topical pharmaceutically acceptable solution to a human in need thereof, wherein the pharmaceutically acceptable solution comprises:
(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 method of claim 1 , wherein the concentration of levcromakalim is about 0.075% w/v (about 2.6 mM).

3 . The method of claim 1 , wherein the concentration of levcromakalim is about 0.03% w/v (about 1 mM).

4 . The method of claim 1 , wherein the concentration of levcromakalim is about 0.015% w/v (about 0.5 mM).

5 . The method of claim 1 , wherein the ethoxylated glycerol ester is polyoxyl-ethylated castor oil.

6 . The method of claim 5 , wherein the concentration of polyoxyl-ethylated castor oil is about 4% w/v.

7 . The method of claim 1 , wherein the polyethoxylated furanose fatty acid ester is polysorbate 80.

8 . The method of claim 7 , wherein the concentration of polysorbate 80 is about 1% w/v.

9 . The method 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 method of claim 9 wherein the concentration of poloxamer 407 is about 0.1% w/v.

11 . The method of claim 1 , wherein the polyol is mannitol.

12 . The method of claim 11 , wherein the concentration of mannitol is about 3.3% w/v.

13 . The method of claim 1 , wherein the polymeric lactam is polyvinylpyrrolidone (PVP).

14 . The method of claim 13 , wherein the polyvinylpyrrolidone (PVP) is povidone K-30.

15 . The method of claim 14 , wherein the concentration of povidone K-30 is about 2% w/v.

16 . The method of claim 1 , wherein the phosphate buffer is a sodium phosphate monobasic buffer, sodium phosphate dibasic buffer, or a mixture thereof.

17 . The method of claim 1 , wherein the composition further comprises a pH adjusting agent.

18 . The method of claim 17 , wherein the pH adjusting agent is hydrochloric acid.

19 . The method of claim 1 , wherein the pH of the composition is about 6.5.

20 . The method of claim 1 , wherein the ocular disorder is primary open angle glaucoma (POAG).

21 . The method of claim 1 , wherein the ocular disorder is ocular hypertension (OHT).

22 . A method of treating an ocular disorder comprising administering an effective amount of an aqueous clear ocular topical pharmaceutical solution to a human in need thereof, wherein the pharmaceutical solution comprises:
(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 . The method of claim 22 , wherein the ocular disorder is primary open angle glaucoma (POAG).

24 . The method of claim 22 , wherein the ocular disorder is ocular hypertension (OHT).

25 . A method of treating an ocular disorder comprising administering an effective amount of an aqueous clear ocular topical pharmaceutical solution to a human in need thereof, wherein the pharmaceutical solution comprises:
(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.

26 . The method of claim 25 , wherein the ocular disorder is primary open angle glaucoma (POAG).

27 . The method of claim 25 , wherein the ocular disorder is ocular hypertension (OHT).

28 . A method of treating an ocular disorder comprising administering an effective amount of an aqueous clear ocular topical pharmaceutical solution to a human in need thereof, wherein the pharmaceutical solution comprises:
(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.

29 . The method of claim 28 , wherein the ocular disorder is primary open angle glaucoma (POAG).

30 . The method of claim 28 , wherein the ocular disorder is ocular hypertension (OHT).

Assignees

• Qlaris Bio Inc
• Mayo Found Medical Education & Res

Inventors

• Htoo Thurein M
• Fautsch Michael P
• Allred Gary
• Casale Ralph
• Wirostko Barbara M

Classifications

• A61K47/44

  Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14) · CPC title

• A61K47/32

  Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• A61K47/14

  Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters · CPC title

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title