Claims for Patent: 12,409,183

Summary for Patent: 12,409,183

Title:	Method of using iloprost for treating frostbite
Abstract:	The present disclosure generally relates to treatment of frostbite by intravenous injection or intravenous infusion of iloprost or a pharmaceutically acceptable salt thereof.
Inventor(s):	Kevin A. CHRISTAL, Christa-Lynn J. VAMPOLA, Wade W. BENTON
Assignee:	BTG International Inc
Application Number:	US18/776,438
Patent Claims:	1. A method of treating severe frostbite in a subject, comprising a) diluting about 1 mL of a pre-dilution composition comprising a concentrated solution of iloprost, said concentrated solution of iloprost comprising (1) about 0.1 mg/mL of iloprost, or a pharmaceutically acceptable salt or a stereoisomer thereof, (ii) about 0.24 mg/mL of tromethamine, (iii) sodium chloride, and (iv) ethanol, in 0.9% sodium chloride, said diluted composition having a final concentration of about 1 μg/mL of iloprost, or a pharmaceutically acceptable salt or a stereoisomer thereof; and b) administering the diluted composition to the subject by intravenous infusion, wherein the administration comprises a titration step on a first day of administration, said titration step being repeated on the second and third days of administration; wherein the administration on the first day comprises a starting dose and increments by which the dose is increased to a maximum dose, and wherein the administration on the second and third days comprises the same starting dose and increments of increase as on the first day, but wherein the maximum dose achieved on each day may be different; wherein the diluted composition is administered to the subject for a maximum of 8 consecutive days; and wherein the method reduces the risk of digit amputation in the subject when compared with standard of care treatments for severe frostbite. 2. The method of claim 1, wherein the administering is at one or more doses between about 0.25 ng/kg/min and about 2.0 ng/kg/min. 3. The method of claim 1, wherein the administering comprises a titration step on a first day of administration with a starting dose of about 0.25 ng/kg/min or about 0.5 ng/kg/min. 4. The method of claim 3, wherein the starting dose is about 0.5 ng/kg/min, and wherein the subject does not have a pre-existing Child-Pugh Class B or Child-Pugh Class C hepatic impairment. 5. The method of claim 3, wherein the starting dose is about 0.5 ng/kg/min and the dose is decreased to about 0.25 ng/kg/min at the beginning of the titration step when the subject has a renal impairment with eGFR less than 30 mL/min/m2 and the subject cannot tolerate the starting dose of about 0.5 ng/kg/min. 6. The method of claim 3, wherein the starting dose is about 0.25 ng/kg/min, and wherein the subject has a Child-Pugh Class B or Child-Pugh Class C hepatic impairment. 7. The method of claim 3, wherein the dose is increased in increments of about 0.5 ng/kg/min every about 30 minutes during the titration step until a maximum dose is reached. 8. The method of claim 7, wherein the maximum dose is about 2.0 ng/kg/min or a highest dose the subject can tolerate between about 0.25 ng/kg/min and about 2.0 ng/kg/min. 9. The method of claim 3, wherein the titration step comprises decrease in the dose if the subject has a dose-limiting reaction. 10. The method of claim 1, wherein the diluted composition is administered continuously each day during a treatment period, wherein the continuous administration per day is for about 6 hours. 11. The method of claim 8, wherein the maximum dose or highest dose is maintained for the remainder of a treatment period after performing the titration step on the first day, the second day, and the third day. 12. The method of claim 1, wherein the severe frostbite is a stage 3 or a stage 4 frostbite. 13. The method of claim 1, wherein the pre-dilution composition is in a single dose vial in an amount of about 1 mL. 14. A method of treating severe frostbite in a subject, comprising a) diluting about 1 mL of a pre-dilution composition comprising a concentrated solution of iloprost, said concentrated solution of iloprost comprising (i) about 0.1 mg/mL of iloprost, or a pharmaceutically acceptable salt or a stercoisomer thereof, (ii) about 0.24 mg/mL of tromethamine, (iii) sodium chloride, and (iv) about 8.1 mg/mL of ethanol, in 0.9% sodium chloride, said diluted composition having a final concentration of about 1 μg/mL of iloprost, or a pharmaceutically acceptable salt or a stereoisomer thereof; and b) administering the diluted composition to the subject by intravenous infusion, wherein the administration comprises a titration step on a first day of administration, said titration step being repeated on the second and third days of administration; wherein the administration on the first day comprises a starting dose and increments by which the dose is increased to a maximum dose, and wherein the administration on the second and third days comprises the same starting dose and increments of increase as on the first day, but wherein the maximum dose achieved on each day may be different wherein the diluted composition is administered to the subject for a maximum of 8 consecutive days; and wherein the method reduces the risk of digit amputation in the subject when compared with standard of care treatments for severe frostbite. 15. A method of treating severe frostbite in a subject comprising a) diluting about 1 mL of a pre-dilution composition comprising a concentrated solution of iloprost, said concentrated solution of iloprost comprising (i) about 0.1 mg/mL of iloprost, or a pharmaceutically acceptable salt or a stereoisomer thereof, (ii) about 0.24 mg/mL of tromethamine, (iii) sodium chloride, and (iv) about 8.1 mg/mL of ethanol, in 0.9% sodium chloride, said diluted composition having a final concentration of about 1 μg/mL of iloprost, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the composition has a pH of 8.3; and b) administering the diluted composition to the subject by intravenous infusion, wherein the administration comprises a titration step on a first day of administration, said titration step being repeated on the second and third days of administration; wherein the administration on the first day comprises a starting dose and increments by which the dose is increased to a maximum dose, and wherein the administration on the second and third days comprises the same starting dose and increments of increase as on the first day, but wherein the maximum dose achieved on each day may be different; wherein the diluted composition is administered to the subject for a maximum of 8 consecutive days; and wherein the method reduces the risk of digit amputation in the subject when compared with standard of care treatments for severe frostbite. 16. The method of claim 1, wherein the pre-dilution composition comprises about 0.242 mg/mL of tromethamine. 17. The method of claim 1, wherein the pre-dilution composition has a pH of about 8.3. 18. The method of claim 1, wherein the pre-dilution composition is formulated as a sterile solution. 19. The method of claim 1, wherein the pre-dilution composition comprises no preservatives. 20. The method of claim 1, wherein the diluted composition comprises about 100 mL of the 0.9% sodium chloride. 21. The method of claim 1, wherein the diluting is performed in an IV bag. 22. The method of claim 21, wherein the infusion bag comprises about 100 mL of the 0.9% sodium chloride. 23. The method of claim 21, wherein the infusion bag is made of polyvinyl chloride (PVC). 24. The method of claim 1, wherein the method reduces the risk of digit amputation by at least 15%, at least 20%, at least 25%, or at least 30% when compared with standard of care treatments for frostbite. 25. The method of claim 1, wherein the method reduces the risk of digit amputation by about 35% to about 50% when compared with standard of care treatments for severe frostbite. 26. The method of claim 25, wherein the method reduces the risk of digit amputation by about 40% when compared with standard of care treatments for severe frostbite. 27. The method of claim 12, wherein the stage 3 frostbite is characterized by the presence of at least one digit of the subject having a lesion that extends just beyond a proximal phalanx. 28. The method of claim 12, wherein the stage 4 frostbite is characterized by the presence of at least one digit of the subject having a lesion extending proximal to a metacarpal joint or a metatarsal joint.